ANTIPHLOGISTIC p-AMINOARYLALKANOL DERIVATIES

ABSTRACT

As antiphlogistic agents having activities as 1-perhydroazepinyl; as indomethacin and much lower acute toxicities, there are provided compounds of the formula WHEREIN R1 represents a free, esterified or etherified OH-group; R2 represents H, CH3 or C2H5; R3 represents H, F, Hal, NO2, NH2, CH3, C2H5, CH3S or C2H5S; R4 and R5 represent H or, together, -CH=CH-CH=CH; Q is pyrrolidino, piperidino or homopiperidino, 1-perhydroazepinyl; and Hal represents Cl, Br or I; With the provision that when R4 and R5 represent H, R3 does not represent H, as well as the acid addition salts and quaternary ammonium salts thereof.

United States Patent Borck et al.

[451 June 13, 1972 ANTIPHLOGISTIC P- AMINOARYLALKANOL DERIVATIES [72] Inventors: Joachim Borck; Johann Dahm; Volker Kopp Josef Kramer; Gustav Schoree; Jan Willem Herman Hovy; Ernst Schorscher, all of Darmstadt, Germany Merck Patent Gesellschaft mit beschrankter Haftung, Darrnstadt, Germany 22 Filed: July 25,1969

21 Appl.No.: 845,076

[73] Assignee:

Related US. Application Data [63] Continuation-in-part of Ser. No. 746,326, July 22,

260/326.5 R, 260/326.82, 260/293.79, 260/326.5 L, 260/575, 260/477, 260/490, 260/468 R, 260/456,

260/618 R, 260/611 A, 260/611 F, 260/476 R,

260/476 C, 260/488 CD, 260/141, 260/486 H,

260/475 R, 260/485 R, 260/293.64, 260/293.71, 260/293.69, 260/326.5 G, 260/247.1, 260/247.5 R,

260/243 B, 260/268 PH, 260/268 H, 260/293.8,

260/293.72, 260/293.67, 260/326.5 J, 260/326.5 D, 260/239.3 R, 260/239.76, 260/376.5 FL

[51] Int. Cl. ..C07d 29/36 [58] Field of Search ..260/293.47, 293.4, 294.3 A, 260/294.7, 294,7 M, 239 B, 326.3, 326.5 S, 326.5

[56] References Cited UNITED STATES PATENTS 2,075,359 3/1937 Salzberg et a] ..424/250 2,573,933 11/1951 Schmerling et al 60/2947 M OTHER PUBLICATIONS Hackh's Chemical Dictionary, 4th Ed. (1969) pp. 16 and 62 Primary Examiner-Henry R. .liles Assistant ExaminerS. D. Winters Attorney-J. William Millen and Millen, Raptes and White [5 7] ABSTRACT As antiphlogistic agents having activities as l-perhydro-azepinyl; as indomethacin and much lower acute toxicities, there are provided compounds of the formula wherein R represents a free, esterified or etherified OH-group; R represents H, CH or C H R represents H, F, Hal, N0 NH CH C H CH -,S or

C H S; R and R represent H or, together, CH CHCH Q is pyrrolidino, piperidino or homopiperidino, l-perhydroazepinyl; and Hal represents Cl, Br or I; With the provision that when R, and R represent H, R does not represent H, as well as the acid addition salts and quaternary ammonium salts thereof.

31 Claims, No Drawings ANTIPHLOGISTIC P-AMINOARYLALKANOL DERIVATIES This is a continuation-in-part of our prior filed application Ser. No. 746,326, filed July 22, 1968.

This invention relates generally to p-amino-arylalkanol derivatives, and in particular to a group of compounds exhibiting highly active antiphlogistic effects.

Accordingly, one aspect of this invention is to provide a group of novel compounds and processes for their production.

A further aspect is to provide therapeutic pharmaceutical compositions and methods of administering same to animals.

Upon further study of the specification and appended claims, other aspects and advantages of this invention will become apparent.

In accordance with the above aspects, there are provided compounds of the following Formula 1:

wherein R represents a free, esterified or etherified OH-group;

R represents H, CH or C H R represents H, F, Hal, N NH CH C H CH S C H S;

R,, and R represent H or, together, -CH CHCH CH; Q is pyrrolidino, piperidino or homopiperidino, lperhydroazepinyl; and

Hal represents Cl, Br or I;

with the rovision that when R, and R represent H, R, does not represent H,

as well as the acid addition salts and quaternary ammonium salts thereof.

It has been discovered that these compounds are physiologically compatible and exhibit highly active antiphlogistic effects accompanied by analgesic and antipyretic effects. In addition, these compounds exhibit bacteriostatic, bactericidal, antiprotozoal, diuretic, blood-sugar-lowering, choleretic, cholesterol-level-lowering and radiation-protective effects. (For the purposes of this invention, antiphlogistic is intended to be synonymous with antiinflammatory.)

In comparison to the known antiphlogistic Ibufenac" (pisobutyl-phenylacetic acid), somewhat similar in constitution, the following table demonstrates that compounds of this invention in a UV erythema test on guinea pigs have antiphlogistic activities ranging from 30 to 100 fold higher.

lbufenac (Comparison Substance) l 2( 3-chloro-4-piperidinophenyl)-propanol (A) 100 2-(4-piperidinonaphthyl-l )-propanol (B) 100 2-( 3-chloro-4-piperidinophenyl)-propylmethyl ether (C) 100 2-( 3-bromo-4-piperidinophenyl)-propanol (D) 100 2-( 3-methyl-4-piperidinophenyl)-propanol (E) 100 2-( 3-chloro-4-piperidinophenyl )-propyl butyrate (F) 100 2-( 3-chloro-4-piperidinophenyl )-propyl acetate (G) 30 In addition, from the standpoint of comparative acute toxicities, the compounds of this invention are about the same as lbufenac (tested on mice). This means that the therapeutic index of the above compounds of this invention is also about 30 100 times higher,

Even comparing the compounds of this invention with other antiphlogistics having far different chemical structures, again Analgesic writhing Phenylbutazone Test (mouse) (Comparison Substance) l l Kaolin Edema Test (rat) O mUO #wwrororow As compared to the conventional powerful antiphlogistic indomethacin (1-p-chlorobenzoyl-2-methyl-5-methoxy-indolyl- 3-acetic acid), the compounds of this invention, having approximately equally high activities, are distinguished by toxicities which are generally substantially lower. For example, compounds A, B, C and F have about the same effectiveness on the UV erythema of the guinea pig as indomethacin, but they possess only about at most one-twentieth of the acute toxicity of indomethacin (on mice).

Thus, the compounds of Formula 1, as well as the acid addition salts and quaternary ammonium salts thereof constitute an important advance as antiphlogistic drugs. Of the compounds of Formula 1, the following selected subgeneric groups of compounds of Formula 1, as well as the acid addition salts and quaternary ammonium salts thereof, represent preferred classes of the present invention: (residues not mentioned having the definitions previously indicated for Formula I).

Definition Subgeneric group Residue (1) R is OH, acyloxy or alkylsulfonyloxy of respectively 1-6 carbon atoms, arylsulfonyloxy of 6-40 carbon atoms or alkoxy of 1-4 carbon atoms;

is OH;

is H, Cl, Br, CH CH S, or C,H,S

except when R, and R represent H R is not H;

represent H;

together represent CH CH- CH CH--;

is piperidino;

is OH, acyloxy or alkylsulfonyloxy of respectively 1-6 carbon atoms, arylsulfonyl-oxy of 6-10 carbon atoms or alkoxy of l-4 carbon atoms,

is Cl, Br, CH CH S or C H 8 and represent H;

is CH, acyloxy or alkylsulfonyloxy of respectively 1-6 carbon atoms, arylsulfonyloxy of 6 l0 carbon atoms or alkoxy of l-4 carbon atoms,

is H and together represent -CH CH- CH CH-,

is OH, acyloxy or alkylsulfonyloxy of respectively 1-6 carbon atoms, arysulfonyloxy of 6-10 carbon atoms or alkoxy of 14 carbon atoms,

R, is CH,,

( 1 l) R, is CH, acyloxy or alkylsulfonyloxy of respectively 1-6 carbon atoms, arysulfonyl-oxy of 6-10 carbon atoms or alkoxy of 1-4 carbon atoms,

R, is CH,,,

R is H,

R, 84 R, together represent CH CH CH CH, and

Q is piperidino;

( 12) R, is OH,

R, is Cl, Br, CH CH;,S or CgHsS,

and R 84 R, represent H; 13) R, is OH R is H,and R, 8L R together represent CH CH CH= CH', 14) R, is OH,

R, is CH;,, R, is Cl, Br, CH CH S or C H .,S, R, & R, represent H, and

is piperidino.

To produce the compounds of Formula I as well as the acid addition and quaternary ammonium salts thereof, any one of the following processes can be used:

a. a compound otherwise corresponding to Formula l but containing, additionally or in place of H-atoms, at least one reducible group and/or at least one C-C unsaturated bond and/or at least one C-N-unsaturated bond, is treated with a reducing agent;

b. a compound of Formula 2 Z represents M is an equivalent of a metallic atom or an organo-metallic residue, and R is an etherified or metallized OH-group, is reacted with a compound of Formula 3 R X 3 wherein R is CH, or C H and X is Hal or reactively esterified OH-group, such as sulfuric or sulfonic acid ester; or a compound of Formula 4 Z-CHXCH R, 4 is reacted with a compound of Formula 5 R, M 5 c. a compound of Formula 6 Rt s wherein X, represents X. OH or an optionally monoor dialkylated NH,-group. and A represents the group CHR,-CH R, is reacted with an amine of Formula 7 Q H 7 or an amine of Formula 8 I ia 8 is reacted with a compound of Formula 9 wherein n represents 4, 5 or 6, and

both residues X can also represent, together, 0 or S;

d. the substituent R or Q is introduced into a compound of Formula 1 containing, in place of R or Q, respectively, hydrogen, by treatment with halogenating, nitrating, aminating, alkylating or thioalklating agents;

. a compound of Formula 1 wherein SM, replaces R, (M, representing H or an equivalent of a metallic atom) is treated with alkylating agents;

. a compound otherwise corresponding to Formula 1 but having, in place of one or several double bonds, one or several saturated C-C bonds and/or, in place of the residue R,, a substituent which can be oxidized to R,, is treated with dehydrogenating or oxidizing agents, respectively;

g. a compound of Formula 10 ZCHR CH, X 10 wherein X, represents X or a diazonium grouping, is reacted with a compound of Formula 1 l R, OM, 11 wherein R is H, alkyl, aralkyl, aryl or acyl of preferably up to seven carbon atoms, and

M, is H or M; h. an organometallic compound of Formula l2 Z M I2 is reacted with a compound of Formula 13 X CHR CH,-- X, 13 wherein X, is Hal, X is OR,,, or X and X, together represent 0; i. an organometallic compound of Formula 14 Z-CHR,M I4

is reacted with formaldehyde, or with a formaldehyde derivative of Formula 15 X CH OR 15 wherein X, represents Hal or CR j. a compound of Formula 16 2-H 16 is reacted with a compound of Formula l7 X CHR CH R, 17

wherein X, and R, together can also represent 0; or that the compound of Formula 16 is reacted with a corresponding olefin in the presence of a Lewis acid, and/or that, optionally, in a compound of Formula 1 an esterified or etherified hydroxy group is liberated by treatment with hydrolyzing or hydrogenolyzing or thermolyzing agents; and/or a free hydroxy group is esterified or etherified by treatment with esterifying or etherifying agents; and/or a nitro group is reduced to the amino-group; and/or an amino group, after having been converted into a diazonium salt, is replaced by F, Hal, N0 CH S or C H S and/or a compound of Formula 1 is converted by treatment with acids or alkylating agents into the physiologically compatible acid addition salts or quaternary ammonium salts thereof; and/or racemates of Formula 1 are separated into the optical antipodes thereof; and/or compounds of Formula 1 are liberated from the acid addition salts thereof by treatment with a base.

In the above-mentioned compounds, R represents, in addition to OH, preferably an OH-group esterified by a saturated or unsaturated aliphatic, cycloaliphatic, aromatic or heterocyclic, substituted or unsubstituted carboxylic acid or sulfonic acid. Preferred carboxylic acids are of one to 18, preferably one to six carbon atoms, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, isocaproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, crotonic acid, oleic acid, cyclohexanecarboxylic acid, cyclohexylacetic andpropionic acid, benzoic acid, phenylacetic andpropionic acid, picolinic acid, nicotinic acid, isonicotinic acid or furan- Z-carboxylic acid.

Of special significance are those esters containing a groups which renders the compound water soluble, such as carboxyl, hydroxyl, or amino-group, since such compounds can be employed for the preparation of aqueous solutions especially in the form of the ester salts thereof. The thus-obtainable mono-esters or hydroxy or amino esters are derived, for example, from dicarboxylic acids, such as oxalic, malonic, succinic, maleic, glutaric, dimethylglutaric, adipic, pimelic, acetonedicarboxylic, phthalic, tetrahydrophthalic, hexahydrophthalic or diglycolic acid, hydroxycarboxylic acids, such as glycolic acid or aminocarboxylic acids, such as diethylaminoacetic acid or aspartic acid.

Preferred sulfonic acid esters are those derived from alkylsulfonic acids of one to six carbons atoms, e.g., methane-or ethanesulfonic acid, and arylsulfonic acids of six to carbon atoms, for example, benzene-, p-toluene-, and land 2- naphthalenesulfonic acid.

R can also represent an Ol-l-group esterified by an inorganic acid, such as sulfuric acid or phosphoric acid, as well as ester salt groups (e.g., sodium salt group) derived from such an ester.

R can furthermore represent an etherified OH-group, preferably alkoxy of one to 12, preferably one to four carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, rz-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy, as well as amyloxy, isoamyloxy, n-heptyloxy, n-hexyloxy, n-octyloxy, ndecyloxy, n-dodecyloxy; and also alkenyloxy or alkynyloxy of preferably up to 12, particularly up to four, carbon atoms, such as vinyloxy, allyloxy, propargyloxy, or butenyloxy; aryloxy or preferably six to l2 carbon atoms, e.g., phenoxy, 0-, mor p-tolyloxy, land 2-naphtyloxy; as well as aralkoxy of preferably seven to l2 carbon atoms, such as benzyloxy, pmethylbenzyloxy, land 2-phenyl-ethoxy or 1- or 2-naphthylmethoxy. in this connection, the alkoxy, alkenyloxy, alkynyloxy, aryloxy or aralkoxy residue can be optionally monoor polysubstituted, particularly by hydroxy; lower alkoxy of one to four carbon atoms, such as methoxy, ethoxy or n-butoxy; halogen, such as F, Cl, Br or I; amino, substituted amino, such as monoalkylamino or dialkylamino (wherein the alkyl groups are preferably of one to four carbon atoms); heterocyclic residues, such as pyrrolidino, piperidino, homopiperidino, morpholino, thiomorpholino, N-alkylpiperazino (wherein the alkyl group is of 14 carbon atoms), N-phenyl-piperazino, N-(hydroxyalkyl)-piperazino, mercapto or alkyl-mercapto (of one to four carbon atoms).

Accordingly, typical ethers of Formula 1 are the 2-hydroxyethyl-, 2-hydroxypropyl-, 3-hydroxypropyl-, 2-methoxyethyl-, 2-ethoxyethyl-, 3-oxa-5-hydroxypentyl-, 3-oxa-5-methoxypentyl-, 3-oxa-5-butoxypentyl-, 3,6-dioxa-8-hydroxyoctyl-, 3,6-

dioxa-8-ethoxyoctyl-, 3 ,6-dioxa-8-methoxyoctyl-, 3-oXa-5- ethoxypentyl-, 2-aminoethyl-, 3-aminopropyl-,2- dimethylaminoethyl-, 2-diethylaminoethyl, 2- di-npropylaminoethyL, 3-dimethylaminopropyl-, 3- diethylaminopropyl-, Z-methyl-3-diethylaminopropyl-, N- methylpiperidyl-4-, N-methylpiperidyl-3-methyl-, 2-( N- methyl-piperidyl-Z- )ethyl-, 2-piperidinoethyl-, 2-pyrrolidinoethyl-, 2-homopiperidinoethyl-, 2-morpholinoethyl-, 2-thiomorpholinoethyl-, 2-N(-methylpiperazino)-ethyl-, 2-(N- ethylpiperazino)-ethyl-, 22-( N-phenyl-piperazino)-ethyl-, 2-

6 (N-Z-hydroxyethylpiperazion)ethyl-, homopiperazino)-ethyl-, 3-piperidino-propyl-, 3-pyrrolidinopropyl-, 3-( N-methylpiperazino )-propyl,3-( N-ethylpiperazino )-propyl-,3-( N-phenylpiperazino-propyl )-,3- morpholinopropyl-, 3-thiomorpholinopropyl-, 2-morpholinopropyl-, 2-piperidinopropyl-, 2-pyrrolidinopropyl-, 2-N- methylpiperazino)-propyl-, 2-methyl-3-moropholinopropyl-,2 -methyl-3-piperidinopropyl-,Zmethyl-3-pyrrolidinopropyl-, 4- dimethylaminobutyl-, 4-diethylaminobutyland 2-mercapmethyl-ethers of the alcohols of Formula 1 (R OH). Furthermore, the tetrahydro-Z-furyl and tetrahydro-Z-pyranyl-ethers are of interest. Since the spectra of physiological activities of the esters and ethers covered by Formula 1 are largely identical to that of the corresponding alcohol, it may be assumed that the ester or ether portion of the molecule is metabolized in the body to yield a free hydroxy group, before any therapeutic action occurs. With other words, it appears that the nature of the ester or ether portion of the molecule is of little relevance with respect to physiological activity.

Comprehensive details of the aforementioned processes for producing the compounds of the invention are set forth as follows:

a. it is possible to obtain a compound of Formula I by commencing with a starting material containing, in addition or in place of H-atoms, one or several reducible groups and/or C Cand/or C Ndouble bonds and/or C C triple bonds, and treating this starting material with reducing agents.

Groups which can be replaced by hydrogen are, in particular, Hal; oxygen in an N-hydroxy-, epoxy-, sulfynylor carbonyl-group; sulfur in a thiocarbonyl group; hydroxyl; mercapto; amino; and hydroxyl, mercapto or amino substituted by a hydrocarbon residue. It is basically possible to cdnvert com pounds containing only one of the above-mentioned groups or unsaturated bonds, or those containing side-by-side two or several of these groups or unsaturated bonds, into a compound of Formula 1 in accordance with reducing methods described in the literature. Preferably, catalytically activated or nascent hydrogen is employed for this purpose, or complex metallic hydrides, to which can be added, for the production of ethers from esters, specific catalysts, such as BF or AlCl furthermore, reducing methods can be employed in accordance with the conventional Clemmensen, Meerwein- Ponndorf, or Wolff-Kishner reactions.

Preferred starting materials for the reduction are, in particular, those otherwise corresponding to Formula 1, but containing, in place of CH R,, a higher-oxidized residue, such as, for example, an aldehyde, carboxyl or carboxylic acid ester residue, or also a carboxylic acid halogenide, anhydride, azide, amide, acetal or ozonide group. Typical starting sub stances correspond, for example, to the formula ZCHR R wherein R represents CHO, COOH, COOAlkyl (wherein the alkyl group is preferably of one to four carbon atoms), furthermore COl-lal, CO-O-Acyl (wherein acyl represents preferably ZCHR CO or COOAlkyl), CON CH(OR or 2-( N-methyl- O CH (R7)i Thus, for example, 2-(3-chloro-4-piperidionophenyl)- propanol is obtained from a-(3-chloro-4-piperidinophenyl)- propionic acid or the ethyl ester thereof (with LiAlH or 2- (3-chloro-4-piperidinophenyl)-propylethyl ether is obtained (from the ester, with LiAiH4/ 3); from 2-(3-methyl-4- piperidinophenyl)-propanal, 2-(3-methyl-4-piperidinophenyl)-propanol is obtained with iron powder in aqueous acetic acid; a-(3-methyl-4-pyrrolidinophenyl)-propionic acid azide yields, with NaBl-L, 2-(3-methyl-4-pyrrolidinophenyl)- propanol; from a-(3-bromo-4-piperidiono-phenyl)-propionyl chloride, 2-(3-bromo-4-piperidinophenyl)-propanol is obtained with NaAll-L; a-(3-fluoro-4-piperidinophenyl)-butyric acid amide results, with Na in ethanol, in 2-(3-fluoro-4- piperidinophenyl )-butanol; a-( 3-chloro-4-pyrrolidinophenyl)- propionyl-ethyl carbonate results in 2-(3-chloro-4-pyrrolidinophenyl )-propanol with LiAll-L.

Furthermore, it is possible, for example to reduce, with catalytically activated hydrogen, Z-hydroxy- (on CuCr O 2- chloro-, 2-bromoor 2-iodo- (on Pt), 2mercapto- (on Raney Ni), 2-amino-, 2-benzyloxyor 2-benzylamino- (on Pt), 2-oxo- (on PdCl or 2-thio2( 3-methyl-4-piperidinophenyl)-ethanol (on Raney Ni), or the ethyl ether thereof, to 2-(3-methyl-4- piperidinophenyl)-ethanol, or the ethyl ether thereof.

The same alcohol is obtained by reduction also, for example, from 3-methyl-4-piperidino-a-chloro-phenylacetic acid ethyl ester with LiAll-l It is also possible to reduce correspondingly substituted Zmethyleneor Z-ethylidene-phenyl alkanols, e.g., those of the formula Z-C CHR )CH R, (wherein R represents H or CH to the compounds of this invention. Thus, it is possible to obtain, for example, by hydrogenating 2-(3-chloro-4- piperidinophenyl)-2-propenol or the methyl ether or acetate thereof, on Pd-charcoal, the compound 2-( 3-chloro-4- piperidinophenyl)-propanol or the methyl ether or acetate thereof, respectively; or from 2-( 3-methyl-4-piperidinophenyl)-2-butenol or the ethyl ether or acetate thereof, the compound 2-( 3-methyl-4-piperidino-phenyl)-butanol or the ethyl ether or acetate thereof; or from 2-(4-piperidinonaphthyl-l 2 propenol the 2-( 4piperidinonapthyl-l )-propanol.

However, the starting compounds can also be alkylidene compounds which have, in place of the primary alcohol or ether or ester group a function which can be reduced to such a group. Thus, for example, a-(3-methyl-4-piperidinophenyl)- acrylic acid ethyl ester can be reduced to 2-(3-methyl-4 piperidinophenyl)-propanol.

Moreover, compounds containing a keto or lactam group in the heterocyclic ring can be reduced to the compounds of this invention. Thus, for instance, from 2-[3-methyl-4-(2-oxopiperidino)-phenyll-propanol (with LiAlH or from 2-[3- chloro-4-(4-oxo-piperidino)-phenyl]-propanol (according to Clemmensen), or from a-[3-chloro-4-(2-oxo-piperidino)- phenyl]-propionic acid ethyl ester (with LiAlH 2-(3- methyl-4-piperidinophenyl )-propanol or 2-( 3-chloro-4- piperidino-phenyl)-propanol is obtained. Furthermore, it is possible for example, to produce, by hydrogenation, from 2- (3-methyl-4-piperidiono-6-chloro-phenyl)-propanol or from 2-( 6-chloro-4-piperidinonaphthyl-l )-propanol, 2-( 3-methyl-4 -piperidinophenyl)-propanol or 2-( 4-piperidinonaphthyl-l propanol.

Also, suitable ether or ester derivatives of the compounds of Formula 1 can be split reductively, e.g., ethers of the benzyl type, or carbobenzoxy derivatives. Thus, for example, it is possible to obtain from 2-( 3-methyl-4-piperidinophenyl)- propyl-benzyl ether or -pmethyl-benzyl ether, or -triphenylmethyl ether, or -diphenylmethyl ether, or -a-picolyl ether, or from the corresponding carbobenzoxy derivative, 2-( 3- methyl-4-piperidinophenyl)-propanol by hydrogenation on Pd-charcoal.

Epoxides of the formula esters or ethers of the formula ZCR CHR (R in this connection representing an esterified or etherfied OH-group), can likewise be reductively converted into a compound of Formula 1. Thus, for example, 2-(3-chloro-4-piperidino-phenyl)-propanol, or the ethyl ether or acetate thereof is obtained from l-methyll 3-chloro-4-piperidinophenyl )-ethylene oxide (with LiAlH /AlCl or from 2-(3-chloro-4-piperidinohenyD-Lpropenyl-ethyl ether or -1-propenyl acetate (with Na-amalgam Aldehyde ammonia compounds which otherwise correspond to Formula 1 but carry, in the a-positions, with respect to the N-atom of the pyrrolidine, piperidine or homopiperidine ring, one or two hydroxy groups, can be reductively converted into compounds of Formula I, the hydroxy group(s) being removed hydrogenolytically. These aldehyde ammonia compounds are produced as intermediates during the reductive alkylation of amines of Formula 8 with dialdehydes of the formula OCH-(Cl-hM-CHO (m being 2, 3 or 4) in the presence of hydrogen and a hydrogenation catalyst; they are normally not isolated. Rather, the reductive conversion of 8 with dialdehydes is continued directly up to the stage of the compounds of Formula 1.

A variant of the reaction resides in starting with a benzyl alcohol of the formula ZCHR OH, which compound is reacted under hydrogenating conditions with CO in the presence of catalysts, such as cobalt acetate, at a high pressure and temperatures of between 100 and 200 C.; during this process, an intermediate product of a higher oxidation stage, formed therein, is reduced.

It is also possible to reductively convert sulfynyl compounds, such as 2-( 3-methylsulfynyl-4-piperidionophenyl)- propanol into the corresponding thio-ethers. Basically, all those reducing methods can be employed which are described in the literature, depending on which of the above-disclosed starting materials is selected.

For catalytic hydrogenations and/or hydrogenolyses, suitable catalysts are, for example, noble metal, nickel, and cobalt catalysts, and for the reduction of carboxylic acid derivatives also mixed catalysts, such as copper chromium oxide. The noble metal catalysts can be provided on supports (e.g., platinum on charcoal, palladium on calcium carbonate or strontium carbonate), in the form of oxide catalysts (e.g., platinum oxide) or as finely divided metallic catalysts. Nickel and cobalt catalysts are suitably employed in the form of Raney metals, nickel is also utilized on kieselguhr or pumice as the support. The hydrogenation can be conducted at room temperature and normal pressure, or also at elevated temperature and/or elevated pressure. Preferably, the process is carried out at pressures of between 1 and 100 atmospheres, and occasionally, such as during the hydrogenation of esters with Co"-acetate, for example, also at elevated pressures, and at temperatures of between and 200 C., especially between room temperature and +lOO C. The reaction is suitably conducted in the presence of a solvent, such as water, methanol, ethanol, isopropanol, n-butano], ethyl acetate, dioxane, acetic acid or tetrahydrofuran; it is also possible to employ mixtures of these solvents with one another. For the hydrogenation, the free compounds or the corresponding salts can be employed, for example the hydrochlorides or sodium salts.

in the hydrogenation of unsaturated bonds and during the hydrogenolysis of benzyl groups, the process is preferably conducted at normal pressure by terminating the hydrogenation after the stoichiometric quantity of hydrogen has been absorbed. Basically, it is possible to operate under the acidic, neutral or basic conditions. In connection with those compounds containing a C N double bond, a reaction in a neutral medium is preferred.

Generally, the reaction with nascent hydrogen can also be employed as a reducing method. Nascent hydrogen can be produced, for example, by treating metals with acids or bases. Thus, it is possible, for instance, to employ a mixture of zinc with acid or alkaline solution, of iron with hydrochloric acid or acetic acid, or of tin with hydrochloric acid, Likewise suitable is the use of sodium or another alkali metal in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol, or phenol. ln reduction processes involving carboxylic acid derivatives in accordance with Bouveault-Blanc, the reaction is preferably conducted at the boiling temperature of the alcohols employed. Furthermore, it is possible to use an aluminum-nickel alloy in an alkaline-aqueous solution, optionally with the addition of ethanol. Also sodium amalgam or aluminum amalgam in an aqueous-alcoholic or aqueous solution is suitable for the production of nascent hydrogen. The reaction can also be conducted in a heterogeneous phase; in

this connection, it is suitable to employ an aqueous phase and a benzene or toluene phase. The reaction temperatures utilized range between room temperature and the boiling point of the solvent employed.

Especially advantageous reducing agents include complex metal hydrides, such as, above all, LiAll-L and NaBl-L, optionally with the addition of catalysts, such as BF AlCl or LiBr. The reaction is suitably conducted in the presence of an inert solvent, such as ether, tetrahydrofuran, ethylene glycol dimethyl ether, but it is also possible to operate, if desired and especially when utilizing NaBl-L, in aqueous or alcoholic solutions. The reactions are advantageously conducted between 80 C. and the boiling point of the solvent. The thus-formed metallic complexes can be decomposed in a conventional manner, for example with moist ether or an aqueous ammonium chloride solution. Aldehydes of the formula Z-CHR CHO can furthermore be reduced according to Meerwein- Ponndorf; this process is conducted with aluminum alcoholates, preferably aluminum isopropylate or ethylate, in benzene or toluene, for example, and at temperatures between room temperature and the boiling point of the solvent.

Further suitable reducing agents are, for example, sodium dithionite in an alkaline or ammoniacal solution; Iron (II)- hydroxide; tin (ID-chloride; hydrogen sulfide, sulfur hydrides, sulfides and polysulfides; hydriodic acid, or sodium sulfite.

lt is further possible to reduce one or several carbonyl groups to CH -groups in accordance with the methods of Clemmensen or Wolff-Kishner known from the literature. In the reduction according to Clemmensen, the carbonyl compounds are treated, for example, with a mixture of zinc and hydrochloric acid, amalgamated zinc and hydrochloric acid, or tin and hydrochloric acid. The process is conducted either in an aqueous-alcoholic solution or in a heterogeneous phase with a mixture of water and benzene or toluene. The reaction is terminated by heating the reaction mixture to the boiling point of the solvent employed. Moreover, the metal can either by provided first and the acid added thereto dropwise, or, conversely, the acid can be provided and the metal added in batches. The reduction in accordance with Wolff-Kishner can be conducted by treating the carbonyl compounds with anhydrous hydrazine in absolute ethanol, in an autoclave or bomb tube; in this connection, the reaction temperatures can be increased to 250 C. An advantageous catalyst is sodium alcoholate. The reduction can also be varied in accordance with the method of Huang-Minlon, by employing hydrazine hydrate as the reducing agent, and conducting the reaction in a high-boiling, water-miscible solvent, such as, for example, diethylene glycol or triethylene glycol, as well as in the presence of an alkali, such as sodium hydroxide, for instance. The reaction mixture is normally boiled for about 3-4 hours. Thereafter, the water is distilled off, and the residue is heated for some time to temperatures of up to about 200 C. During this procedure, the formed hydrazone is decomposed, and the originally present carbonyl group is converted into a CH group. The Wolff-Kishner reduction can also be conducted at room temperature in dimethyl sulfoxide with hydrazine.

It is furthermore possible to replace Hal-atoms, particularly aromatically bound Hal-atoms, by hydrogen; this is done by converting the corresponding Hal-compounds into the associated organometallic compounds, (e.g., Grignard compounds, and hydrolyzing same with water or dilute acids.

b. It is possible to convert organometallic compounds of Formula 2, particularly the alkali metal, alkaline earth metal, Zn or Cd compounds, or the alkaline earth, Zn or Cd-Hal compounds obtained by the direct metallization, as for example with butyllithium, phenyllithium, NaH, NaNH or metallic Na or Mg, of the corresponding hydrogen or halogen compounds, into compounds of Formula l, with methyl bromide, methyl chloride, -sulfuric acidor -sulfonic acid-esters of Formula 3 in inert solvents, such as benzene, xylene, dioxane or tetrahydrofuran. Typical compounds of Formula 2 are, for example, 1- (3-methyl-4-piperidinophenyl)-2-methoxyethylmagnesium bromide or the lithium alcoholate of piperidinonaphthyl-l )-2-hydroxyethyllithium.

On the other hand, it is possible to alkylate, under analogous conditions, compounds of Formula 4, especially the correspondingly substituted a-chloro-, a-bromoor a-iodo phenylalkanol derivatives, or the a-hydroxy-phenylalkanol derivatives esterified with sulfuric acid derivatives or sulfonic acid derivatives, with metallic compounds of Formula 5, particularly alkali metal derivatives, such as methyllithium or sodium, or ethyllithium or -sodium, or Grignard compounds, such as methylmagnesium bromide or iodide. Typical compounds of Formula 4 are, e.g., l-( 3-methyl-4-piperidinophenyl)-2-methoxyethyl bromide or l-(4-piperidinonaphthyl-l )-2- benzyloxyethyl-p-toluene sulfonate.

c. The reaction of compounds of Formula 6 with amines of Formula 7 (pyrrolidine, piperidine or homopiperidine) or of amines of Formula 8 with compounds of Formula 9 takes place basically in accordance with the conventional exchanging reactions described in the literature.

The reaction can be conducted in the presence or absence of a solvent. Examples of solvents include lower aliphatic alcohols, ethylene glycol, benzene, toluene, chloroform, dichlorobenzene, tetrahydrofuran, dioxane or dimethylformamide. Depending on the starting material employed, the process is carried out at low temperatures, e.g., room temperature, or at elevated temperatures, up to the boiling temperature of the solvent utilized. In individual cases, it can be of advantage to conduct the reaction under pressure (up to 200 atmospheres) or at elevated temperature (up to 320 C. The use of a catalyst, e.g., a base, such as sodium or potassium carbonate, is possible, but not absolutely necessary. Advantageously, the amines are employed in an excess; in case of the reaction of 6 and 7, the amines can simultaneously serve as the solvent.

Preferred starting compounds of Formula 6 are those wherein R is a nitro group, e.g., 2-(3-nitro-4-bromophenyl)- ethanol, -propanol or -butanol; the corresponding 4-chloroand 4-iodo-compounds; as well as the esthers and ethers derived from these substances.

Thus, it is possible, for example, to produce from 2-( 3-nitro- 4-bromophenyl)-propanol or the ethyl ether thereof, or from 2-(3-nitro-4-bromonaphthyl-l )-propanol or the ethyl ether thereof, the corresponding 4-piperidino-, 4-homopiperidinoor 4-pyrrolidinophenyl-propanols, or -naphthyl-l-propanols, or the ethyl ethers thereof, by reaction with piperidine, homopiperidine or pyrrolidine.

Preferred amines of Formula 8 are 2-(3-fluoro-4- aminophenyl)-ethanol, -propanol and -buta.nol; 2-( 3-chloro-4- aminophenyl)-ethanol, -propanol and -butanol; 2-(3-bromo-4 -aminophenyl)-ethanol, -propanol and -butanol; 2-(3-iodo-4- aminophenyl)-ethanol, -propanol and -butanol; 2-(3-nitro-4- aminophenyl)-ethanol, -propanol and -butanol; 2-(3-methyl-4 -aminophenyl)-ethanol, -propanol and -butanol; 2-( 3-ethyl-4- aminophenyl)-ethanol, -propanol and -butanol', 2-(3-methylmercapto-4-aminophenyl)-ethanol, propanol and -butanol; 2- (3-ethylmercapto-4-aminophenyl)-ethanol, -propanol and butanol; 2-(4-aminonaphthyl-l )-ethanol, -propanol and butanol; as well as the esters and ethers derived from these compounds, particularly the lower fatty acid esters and the lower alkyl ethers thereof.

If the starting material is a phenol of Formula 6 (X OH) or a preferably lower aliphatic carboxylic acid ester of such a phenol, the reaction with the amines 7 is suitably conducted in the presence of a catalyst. A suitable catalyst is either a dehydration agent or a dehydrogenation agent, or a mixture of these catalysts. An example for a dehydration catalyst is aluminum oxide, the latter being optionally activated with other suitable oxides. The dehydrogenation agent can be, for example, Raney nickel or the conventional noble metal catalysts, such as, for example, palladium oxide or palladium charcoal.

By means of a transamination, amino groups in the compounds of Formula 6 or 8 can be exchanged by reaction with amines of Formula 7.

The reaction conditions for such a transamination are described in the literature. Advantageously, the process is conducted in the presence of catalysts, such as acids, metal salts, iodine, dehydration agents, hydrogenationdehydrogenation catalysts, or sodium hydrogen sulfide. It is advantageous to conduct the transamination in the presence of an inert solvent; furthermore, it is advantageous to conduct the reaction under elevated pressure as well as at higher temperatures.

As the compound of Formula 9, a dihaloalkane is especially preferably employed, such as 1,4-dichloro-, l,4-dibromoor 1,4-diiodobutane, l,5-dichloro-, 1,5-dibromoor 1,5- diiodopentane, and l,6-dichloro-, l,6-dibromoor 1,6- diiodohexane. However, sulfur or oxygen ring compounds, such as tetrahydrofuran, -pyran, -thiophene or -thiopyran, are likewise suitable for the reaction. The reaction of such sulfur or oxygen ring compounds with amines of Formula 8 is generally conducted under severe conditions, such as, preferably, at temperatures of above 150 C. in an autoclave.

d. In compounds of Formula I wherein hydrogen is in place of the residue R the following substituents can be directly introduced into the 3-position: a. Chlorine For example, by direct reaction with elemental chlorine in an inert solvent, such as water, CCl,,, acetic acid, without or with the addition of specific catalysts, such as, for example, Fecl AlCl SbCl or SnCl, preferably between -10 and 100 C. (as described in the literature), or by reaction in a strongly hydrochloric solution with H O or with NaClO wherein the chlorination is effected by the chlorine produced in the nascent state (as described in the literature), or by reaction with SO Cl in an inert solvent, such as chlorobenzene, in the presence of radical-forming catalysts, such as peroxides, at preferably 80180 C. (as described in the literature), or by reaction with NO Cl or NOCl in CS or hexane;

B. Bromine For example by direct reaction with elemental bromine in an inert solvent, such as, for example, acetic acid or C Cl,, particularly with the addition of specific catalysts having the effect of bromine transfer agents, such as, for example, iron filings, AlCl AlBr FeCl iodine or pyridine, preferably between 30 and 90 C. (as described in the literature), or by reaction with hypobromous acid, acyl hypobromites, N-bromoimides, such as N-bromosuccinirnide, N- bromophthalimide, or other bromine-yielding agents, such as l,3-dibrorno-5,5dimethylhydantoin, in inert solvents, such as nitrobenzene or CS preferably at l to 150 C. (as set forth in the literature), or by reaction with NOBr or NO Br in CS or cyclohexane;

y. Iodine For example, by direct reaction with elemental iodine, especially in the presence of HgO in an inert solvent, such as ethanol, acetic acid or benzene, preferably at temperatures of between 0 and 120 C. (as disclosed in the literature), or by reaction with iodine-alkali metal iodide solutions in the presence of carbonates, acetates, alkali metal hydroxide solutions, ammonia or amines (as described in the literature), or by reaction of mixtures of alkali metal iodides and oxidizing agents, such as alkali metal iodates, alkali metal nitrates or H 0 in inert solvents, such as water, acetic acid or ethanol, the iodine being liberated reacting in the nascent state, or by reaction with C1! in dilute acetic acid, preferably at 50-l00 C. (as described in the literature), or, after mercuration in an aqueous or acetic medium with I-Ig(lI)-acetate to the 3-Hg-O-COCl-l compound and exchange of the organometallic residue against iodine, for example,

by reaction with iodine or iodine-alkali hydroxide solutions (as described in the literature); and 8. Nitro For example by nitration methods as set forth in detail in the literature. The active nitrating agent is the nitronium ion N0 and all nitronium salts, or also reaction mixtures, wherein this nitronium ion is potentially present, can be employed for the nitration of the aromatic nucleus, for example: a mixture of anhydrous nitric acid with BF metal nitrates, such as Cu-, Fe-, Mn-, Coand Ninitrate in a mixture with acetic acid or acetic anhydride; metal nitrates, such as Ag-, Ba-, Na-, K-, NH,- or Pb-nitrate in a mixture with Friedel-Crafts catalysts, such as AlCl FeCl BF and SiCl.,', alkyl nitrates, such as ethyl nitrate, in mixture with concentrated sulfuric acid, HBF, or Lewis acids, such as BCl SnCl.,, PCl AlCl SiCl SbCl or Fecl nitryl fluoride, chloride, bromide, perchlorate or tetrafluoroborate, preferably in the presence of Friedel-Crafts catalysts, such as AlCl FeCl ZrCl or AlBr in solvents such as carbon disulfide, n-pentane or CI-ICl nitric oxides, such as N O N 0. or N 0 in the presence of concentrated H HF or Friedel-Crafts catalysts, such as BF AlCl or FeCl if desired in solvents, such as tetramethylenesulfone or acetic acid. Suitable solvents for these nitration reactions further include nitromethane, nitroethane, nitropropane or acetonitrile. The process is preferably conducted between -20 and +1 20 C.

In addition, the following agents are generally usable for introducing the nitro group into the aromatic nucleus: concentrated nitric acid; mixtures of concentrated sulfuric acid with concentrated or anhydrous nitric acid; alkali nitrates, such as sodium or potassium nitrate, in a mixture with concentrated sulfuric acid; mixtures of concentrated nitric acid with pyrosulfuric acid, fuming sulfuric acid, acetic acid or acetic anhydride; mixtures of nitric acid, sulfuric acid and acetic acid; acetyl or benzoyl nitrate; nitrosulfonic acid, producible by introducing S0 into fuming HNO nitrosylsulfuric acid; nitroguanidine; highly concentrated nitric acid in the presence of dehydration agents, such as P 0 or anhydrous hydrofluoric acid, optionally in solvents, such as nitrobenzene or polychloroethanes. A specific nitration reaction consists in dissolving the substance to be nitrated in a solvent, such as CHCl CH Cl or CCl,, introducing concentrated sulfuric acid so that it forms a layer below the solution, and then adding anhydrous nitric acid in CHCl CI-l Cl or C0,. In general, the reaction is conducted at between 20 and C.

A still further constituent is e. Alkyl, Alkylmercapto or Amino Which can be introduced for example by reaction with the corresponding chloro, bromo, iodo, hydroxy or acyloxy compounds, such as, for example, methyl chloride, bromide or iodide, ethyl chloride, bromide or iodide, methyl or ethyl sulfuric chloride, hydroxylamine or chloramine in accordance with the conditions of a Friedel-Crafts reaction, as described in the literature. Suitable catalysts are Lewis acids, such as AlCl AlBr SnCh, ZnCl FeCl SbCl or HF, and as solvents there are used n-hexane, carbon disulfrde, nitrobenzene, tetramethylene-sulfone or nitroethane.

The reaction is preferably conducted at between 70 and C. In place of the ethyl derivatives, it is also possible to utilize ethylene for the alkylation step, in accordance with Friedel-Crafts, as has been disclosed in the literature.

Analogously, it is possible to introduce Q into a compound otherwise correspondingly to Formula 1 but containing, in place of Q, a hydrogen atom by treatment with a haloamine of the formula Q-Hal Suitable haloamines are especially N- chloropyrrolidine, N-chloropiperidine and N- chlorohomopiperidine. The reaction is conducted as disclosed in the literature, for example in the presence of a Lewis acid, such as AlCl BF or ZnCl in nitrobenzene or CS For example, the 2-(3-methyl-4-piperidinophenyl)-propylmethyl ether is obtained from 2-m-tolyl-propylmethyl ether.

e. Compounds of Formula 1 carrying an Sl-l-group in the 3-position (SH being optionally also present as a salt, especially as the alkali or alkaline earth salt) are alkylated to alkylmercapto compounds, for example, by reaction with ethylene or with alkyl halides, such as methyl chloride, bromide or iodide, ethyl chloride, bromide or iodide, or with equivalent alkyl derivatives, such as alkyl-sulfuric acid esters or alkylsulfonic acid esters, e.g., dimethyl sulfate, diethyl sulfate or methylp-toluenesulfonic acid esters, as well as with diazomethane or diazoethane. The solvents employed in this connection are, for example, water, methanol, ethanol, benzene, tetrahydrofuran, xylene, or mixtures thereof. Often, alkalis are added, such as NaOH or KOl-l in equivalent amounts or in an excess. Usually, the alkylation conditions are observed as described in paragraph (c).

f. Compounds which otherwise correspond to Formula 1 but which contain, in place of the benzene or naphthalene nucleus, a partially or completely hydrogenated benzene or naphthalene nucleus, can be converted into compounds of Formula 1 under dehydrogenating reaction conditions. Examples of the dehydrogenating agents employed are sulfur, selenium, platinum catalysts, palladium catalysts, nickel catalysts or cobalt catalysts (as metals or on supports, such, as, for example, charcoal, CaCO or SrCO or selenium dioxide, dialkyl disulfides, such as diisoamyl disulfide, chloranil, concentrated sulfuric acid or other gently reacting effective oxidation agents, such as FeCl or nitrobenzene. ln favorable cases, even atmospheric oxygen is sufficient to effect the dehydrogenation. Suitable dehydrogenation catalysts further include silver and copper catalysts, individually or in the form of mixed catalysts, cobalt-charcoal catalysts, nickel-aluminum oxide catalysts, as well as many other mixed catalysts, as they are described in the literature for dehydrogenation reactions.

The dehydrogenation processes with sulfur or selenium are preferably conducted with stoichiometric amounts of sulfur or selenium, respectively, since when an excess thereof is employed, secondary reactions may occur. The reaction takes place preferably at temperatures of between 140 and 300 C. Usually, reaction times of lO-lOO hours are required. A dehydrogenation with metal or metallic oxide catalysts is generally conducted in the liquid phase; however, this process can also take place in the gaseous phase, when the substance to be dehydrogenated converts to the gaseous phase at normal or reduced pressure and at the temperatures necessary for the dehydrogenation. The dehydrogenation temperature and duration vary within wide limits, so that reaction temperatures of between 100 and 350 C. and reaction times of between 5 and 100 hours can be required. Suitable solvents are, for example, mesitylene, p-cymene, naphthalene, quinoline, acetanilide, and other high-boiling aromatic compounds. Quinones, such as chloranil can be employed for the dehydrogenation under gentle conditions; heating the compound to be dehydrogenated with chloranil in an inert solvent to 70- 150 C. results in the desired products, Thus, it is possible, for example, to dehydrogenate 2-(4-piperidino-5,6,7,8- tetrahydronaphthyl-l) -propylethyl ether or 2-(4-piperidino- 5,6-dihydronapthyl-l )-propylmethyl ether to the correspond ing naphthalene derivatives.

Also, compounds containing, in place of the residue R in Formula 1 a substituent which can be oxidized to R such as, for example, a boronhydride, boron alkyl, aluminum alkyl group, an alkali metal or an alkaline earth metal halide group, can be oxidized to compounds of Formula 1 by suitable oxidation methods known from the literature. For this purpose, it is ZCR =(IH is reacted with dihoranc under the rules of hydroboration, and the thus-obtained boron alkyl compound is exidized with alkaline H O solution. For this purpose, a complex borohydride, such as NaBH for example, and a Lewis acid, such as BF -etherate, is added to a solution of the olefin in an inert solvent, such as tetrahydrofuran or dior triethylene glycol dimethyl ether, at temperatures of between C. and the boiling point of the solvent, and the thusproduced alkyl borane is split with H 0 optionally after decomposition of the excess complex hydride with water, under the addition of a base, such as NaOH, preferably at temperatures of 20-60 C. In place of the diborane, it is also possible to employ alkyl aluminum compounds which can be added and split by oxidation in an analogous manner.

Furthermore, the phenylethyl metal or halometal compounds of the formula ZCHR CH M, obtainable from the phenylethyl halogenides of the formula ZCHR CH Hal with alkali metals, preferably Li, or alkaline earth metals, preferably Mg, can be treated with oxidation agents in order to convert them into compounds of Formula 1. In a preferred embodiment of this method, oxygen is conducted through a solution of the corresponding Grignard compound of the formula ZCHR CH MgHal in an inert solvent, such as ether, tetrahydrofuran or dioxane at temperatures of 40 to C.

g. The compounds of Formula 1 are obtained by starting with a halogen compound, or a sulfonic acid ester, e.g., a methanesulfonate or a p-toluenesulfonate of Formula 10 and subjecting such compound to hydrolysis, alcoholysis or acidolysis, or reacting same with metal salts or metal alcoholates of the fonnula R OM.

Thus, it is possible, for example, to obtain alcohols of Formula l by saponifying a halogen compound of Formula 10 (X Hal) in an aqueous or aqueous-alcoholic solution or suspension, optionally with the addition of a solubilizer, such as an alcohol, glycol or polyglycol ether. Preferred saponification agents are alkalis, such as NaOI-l or KOH; however, it is also possible to employ slurries of Ca(OH) Pb(OH) or AgOl-l. The saponification is usually conducted at an elevated temperature, e.g., at the boiling temperature of the solvent. However, the halogenide 10 can also be reacted in a non-aqueous reaction medium, by stirring the solution thereof in an inert solvent, such as, for example, acetone, ether, tetrahydrofuran, acetonitrile or benzene, with suspended AgOl-l or Pb(Ol-l) under boiling.

Ethers of Formula 1 are obtained by reacting compounds of Formula 10 in accordance with the methods of the Williamson synthesis with alkali alcoholates or phenolates. Advantageously, the sodium alcoholate is produced by dissolving the necessary amount of sodium in the respective alcohol, and the excess alcohol is employed as the solvent. When the less reactive chlorides or bromides of Formula 10 (X Cl or Br) are employed, then a certain amount of Kl can be added. The reaction mixture is then boiled until neutral. Phenyl ethers are produced by mixing the alcoholic alkali alcoholate solution with an equivalent of the respective phenol and otherwise proceeding with the reaction as has been described in connection with the alkyl ethers. When producing the phenyl ethers, additional solvents which can be employed are water or aque ous alcohols. The alkali alcoholates or phenolates can, however, also be reacted in a suspension with halogen compounds of Formula 10, and in this case inert solvents are utilized, such as ether, tetrahydrofuran, acetone or benzene.

In an analogous manner, esters of Formula I are produced by boiling the substances of Formula 10 in an aqueous, aqueous-alcoholic or alcoholic solution with the alkali salts of the carboxylic acids to be esterified. The addition of triethylamine accelerates the reaction. When it is desired to obtain acetates of Formula 1, then a preferred mode of operation resides in boiling the halogenides or sulfonic acid esters of Formula 10 with solutions of anhydrous sodium acetate in glacial acetic acid. It is also possible, for producing esters of Formula 1, to boil halogen compounds of Formula 10 in inert solvents, such as ether, acetone, chloroform, tetrahydrofuran or benzene, with suspensions of the silver salts or lead salts of the carboxylic acids to be esterified. Diazonium compounds of Formula 10 are produced during the treatment of phenylalkylarnine derivatives of the formula ZCl-lR Cl-l Nl-l with nitrous acid or the derivatives thereof, such as, for example, alkyl nitrites or NOCl. These diazonium compounds are split to phenylalkanol derivatives of Formula 1 in the presence of water, in accordance with methods known from the literature. In this case, a particularly advantageous technique is to combine an aqueous solution of NaNO, with a mineral-acid or acetic acid solution of the amine, at temperatures of -l00 C., and terminating the reaction by heating. The reaction of the phenylalkylamine derivatives with alkyl nitrites can preferably be conducted in inert solvents, such as ether, benzene, tetrahydrofuran, in absolute alcohols, such as methanol or ethanol, or in water-alcohol mixtures; in case alcohols of the formula R OH are employed, it is also possible to obtain ethers of Formula 1 (R, etherified OH-group). If the reaction is conducted in the presence of large amounts of acid, such as acetic acid, it is also possible to obtain as the reaction products esters of Formula 1 (R, esterified OH- group).

h. Compounds of Formula 1 can be obtained by reacting aryl lithium or Grignard compounds of Formula 12 (e.g. 3-methyl-4-piperidinophenyllithium or 4-pyrrolidinonaphthyl-lmagnesium iodide) with epoxides or substituted haloalkanols of Formula 13 (e.g. ethylene oxide, propylene oxide, 2-chloroethanol, 2-bromoethanol, Z-chloropropanol, 2-bromopropanol). Preferably, the process is conducted in inert solvents, such as ether, tetrahydrofuran or dioxane, at temperatures of between 0 and 180 C.

i. Organometallic benzyl derivatives, especially the benzyllithium compounds (e.g., 3-methyl-4-piperidinobenzyllithium or 2-(4-piperidinonaphthyl-l)-propyllithium) or benzylmagnesium halides (e.g. 3-rnethyl-4- homopiperidinobenzyl-magnesium bromide) of Formula 14 can be converted to compounds of Formula 1 with formaldehyde or the derivatives thereof (for example, methylal, chloromethylbenzyl ether or bromomethylethyl ether) of Formula 15; in this connection, the preferred conditions selected are those set forth under (h).

j. Compounds of Formula 1 can be obtained by reacting compounds of Formula 16, such as 2- piperidinochlorobenzene, 2-homopiperidinotoluene or 2- pyrrolidinobromobenzene, preferably in an inert solvent, such as dichloroethane, trichloroethane, CS, or nitrobenzene, under the conditions of a Friedel-Crafts alkylation, with 2-haloalkanols or their esters or ethers of alkylene oxides of Formula 17, or with corresponding olefins, such as allyl alcohol or crotonic alcohol or the esters or ethers thereof. This reaction takes place generally in accordance with methods set forth in the literature. Thus, the reaction is normally conducted first under cooling; thereafter, the reaction can be terminated, if desired, by heating to room temperature or to the boiling point of the solvent. Suitable catalysts are Lewis acids, such as AlCl SbCl FeCl BF ZnCl or mineral acids, such as HF, H 80 H PO, or the anhydrides thereof, such as P 0 In the products of Formula 1 it is also possible, if desired, to replace one or both substituents R, and R, by other substituents.

Thus, esterifted or etherified hydroxy groups can be liberated by means of hydrolysis, hydrogenolysis or thermoly- ,sis, i.e., alcohols of Formula 1 can be obtained by splitting esters or ethers of Formula 1 of this invention.

The saponification of the carboxylic acid esters of alcohols of Formula 1 can be conducted, as disclosed in greater detail in the literature, in a neutral, acidic or alkaline medium, at temperatures of between 20 and 300 C. Acids suitable for hydrolysis are, for example, especially hydrochloric, sulfuric, phosphoric and hydrobromic acid; suitable bases employed in this connection are sodium, potassium, or calcium hydroxide, or sodium or potassium carbonate. The preferred solvents are water, ethanol, methanol, dioxane, tetrahydrofuran, dimethylformamide or mixtures thereof, especially the mixtures containing water. However, it is also possible to saponify the acid derivatives to aminophenylalkanols of Formula 1, for example, in ether or benzene with the addition of strong bases, such as potassium carbonate or without solvents by melting with alkalis, such as potassium and/or sodium hydroxide or alkaline earth hydroxides. The 2-(3-chloro-4-piperidinophenyl)-propylbenzyl carbonate can be converted into the 2-( 3-chloro-4- piperidinophenyl)-propanol, for example, by hydrolysis, as described above, as well as by hydrogenolysis in accordance with the hydrogenation processes disclosed in paragraph (a).

Also ethers of Formula 1 can be converted into alcohols of Formula l in accordance with the ether splitting methods known from the literature. For example, the ethers can be split by treatment with hydrogen bromide or hydrogen iodide in an aqueous or acetic acid solution, by heating with Lewis acids, such as AlCl or boron trihalogenides, or by melting with pyridineor aniline-hydrohalogenides at about 200 C.

A reductive splitting of benzyl, diphenylmethyl or triphenylmethyl ether is conducted in accordance with the same hydrogenation methods or reudcing methods as described in greater detail, inter alia, in paragraph (a). Preferred is the hydrogenolysis with hydrogen in the presence of palladium catalysts. it is also possible to split ethers of Formula 1 wherein R, represents a tert.-alkoxy group, into an alcohol of Formula 1 and an olefin, by heating to temperatures of up to 300 C.

Furthermore, alcohols of Formula 1 (R, OH) can be converted into other compounds of Formula 1 of this invention by esterifying or etherifying the free hydroxy group in accordance with conventional methods described in the literature. Thus, the alcohols of Formula 1 can be esterified with carboxylic acids, without or with the addition of catalysts such as sulfuric acid, hydrogen chloride, phosphoric acid, aromatic sulfonic acids, such as p-toluenesulfonic acid, or acidic ion exchangers, at preferably between 10 C. and the boiling temperature of the acid employed, the latter being usually used in excess. In order to shift the esterification equilibrium, it is also possible to operate in the presence of water-binding agents, such as, for example, with the addition of molecular sieves or anhydrous heavy metal sulfates, such as copper, iron, nickel, cobalt or zinc sulfate. It is also possible to remove the water of reaction by azeotropic distillation; in this connection, hydrocarbons, such as benzene or toluene, or chlorinated hydrocarbons, such as chloroform or 1,2-dichloroethane, are employed as the azeotroping solvents in an advantageous manner.

Esterification reactions take place under very gentle conditions if the water of reaction is chemically bound by the addition of preferably molar amounts of carbodiimides, such as N,N'-dicyclohexyl carbodiimide in inert solvents such as ether, dioxane, benzene or ethylene glycol dimethyl ether, particularly in the presence of bases, such as pyridine.

It is also possible, analogously to the methods described in the literature, to react the alcohols of Formula l or the alkali alcoholates thereof, with the acid halides or anhydrides of the acids to be esterified, in the optional presence of acidneutralizing agents, such as, for example, sodium or potassium hydroxide, sodium or potassium carbonate, or pyridine.

Suitable solvents are inert organic solvents, such as ether, tetrahydrofuran or benzene. It is also possible to utilize excess acid halides or anhydridres as the solvent.

In a preferred manner of conducting the process, a pyridine solution of the alcohol of Formula 1 is combined with the acid halide or the anhydride of the acid to be esterified. Thus, it is possible, for example, to convert the 2-( 3-methyl-4- piperidinophenyl)-propanol, with acetic anhydride in pyridine, into the 2-(3-methyl-4-piperidinophenyl)-propyl acetate.

Esters of Formula 1 can also be obtained by treating alcohols of Formula 1 (R OH) with preferably lower alkyl esters of carboxylic acids, in accordance with the ester interchange methods described in the literature. Preferably, the reaction is conducted in the presence of basic catalysts, such as sodium methylate or ethylate, and the reaction is carried out so that,after the equilibrium has been attained, one reactant is withdrawn from the equilibrium by means of distillation. Thus, it is possible, for instance, by the use of methyl butyrate, to convert 2-(3-methylmercapto-4-piperidinophenyl)- propanol into the 2-(3-methylmercapto-4-piperidinophenyl)- propyl butyrate, with the methanol being distilled off.

If is also possible to esterify alcohols of Formula 1 (R, OH) with ketenes, The reaction is preferably conducted in inert solvents, such as ether, benzene or toluene, and with the addition of acidic catalysts, e.g., sulfuric acid or p-toluenesulfonic acid. Thus, for example from 2(3-chloro-4- piperidinophenyl)-propanol and ketene, the 2-(3-chloro-4- piperidinophenyl)-propyl acetate can be produced,

Esters of Formula 1 are also produced by subjecting diazoketones, e.g., diazoacetone, to a Wolff rearrangement in the presence of alcohols of Formula 1 (R OH) and in the presence of suitable catalysts, such as, for example, Ag O, pyridine or picoline, with nitrogen being split off. The process is conducted in accordance with the general methods known for ester formation according to the Arndt-Eistert reaction. Thus, 2-(3-bromo4-piperidinophenyl)-propyl propionate is produced from 2-(3-bromo-4-piperidinophenyl)-propanol and diazoacetone.

Ethers of Formula 1 can be obtained from alcohols of For mula l by reacting the corresponding alkali alcoholates with alkyl halogenides, alkyl methanesulfonates or alkyl ptoluenesulfonates in accordance with the conventional methods of a Williamson synthesis,

The alkali alcoholates are obtained by stirring the alcohol of Formula 1 in an inert solvent, such as ether, tetrahydrofuran, dioxane or benzene, containing finely dispersed Na, NaNH or NaH, until the development of hydrogen or ammonia is terminated. Thereafter, the alkyl halide, most advantageously the respective iodide, is added and the mixture is boiled for several hours. Thus, it is possible, for example, to produce the 2-(3-methyl-4-piperidinophenyl)-propyl methyl ether from 2- (3-methyl-4-piperidinophenyl )-propanol.

Ethers of Formula 1 are also obtained by allowing alcohols of Formula I to react with diazoalkanes in an inert solvent, such as ether, benzene or toluene, with the addition of catalytic amounts of Lewis acids, such as AlCl BF or FeCl The amount of catalyst added is normally dependent on the reaction velocity, e.g., decelerating reactions can be speeded up by the subsequent addition of further amounts of catalyst.

Finally, alcohols of Formula 1 can also be converted into ethers of Formula 1 by chemically adding these alcohols to olefins. Preferred olefins are those hydrocarbons produced from tertiary alcohols by splitting off water. The addition process is conducted in the presence of acidic catalysts, such as, for instance, mineral acids, tetrafluoboric acid, perchloric acid or BF However, in some cases, basic catalysts, such as, for example, alkali alcoholates, are also suitable. As the solvent, an excess of the olefin can be employed; normally, however, inert solvents are used, such as tetrahydrofuran, dioxane, benzene or toluene. The preferred temperature is the boiling temperature of the respective solvents. Thus, it is possible, for example, to obtain the 2-(3-chloro-4-pyrrolidinophenyl)- propyl-tert.-amyl ether from 2-(3-chloro-4-pyrrolidinophenyl)-propanol and trimethyl-ethylene.

Exchange reactions are also important to produce the compounds of Formula 1. Thus, in compounds of Formula I, wherein R represents an amino group, the latter can be exchanged, after diazotization, for F, Cl, Br, 1, N0 CH S or C H S. The exchange against fluorine is described in the literature. The diazotization is conducted, for example, in anhydrous hydrofluoric acid, and then the reaction mixture is heated; or the poorly soluble diazonium tetrafluoborates, produced in situ, are thermally decomposed, thus producing the 3-fluoro-compounds. Chlorine is exchanged against the diazonium chloride grouping preferably in an aqueous solution in the presence of CO in accordance with the method of Sandmeyer (as described in the literature). The exchange against bromine can likewise be conducted, for example, in accordance with the methods set forth in the literature. The diazonium bromide can be decomposed either in an aqueous solution in the presence of CrBr according to Sandmeyer, or by reaction with bromine to obtain the diazonium perbromide which is subsequently boiled in solvents, such as water or lower alcohols, thus obtaining the desired bromine compounds. However, it is also possible to convert the diazonium bromides, with HgBr into the diazonium mercuric bromides and to decompose the latter thermally to the desired bromine compounds. The exchange of the diazonium iodide group against iodine is already accomplished by gentle heating. However, it is also possible to add catalysts, such as CuI, CuBr or CuCl in order to accelerate the reaction (as disclosed in the literature).

The exchange of the diazonium group, preferably of diazonium tetrafluoborate or diazonium-cobalt (Ill)-nitrite, against the nitro group is described in the literature, and is accomplished, for example, by reaction with alkali nitrites, such as NaNO- or KNO in the presence of catalysts, such as copper oxide or copper hydroxide, the reaction taking place even under ambient conditions. The diazonium salt group can also be exchanged against alkymercapto groups, as disclosed in the literature. For example, the exchange against alkylmercapto groups is effected by reaction with alkylmercaptans, preferably in an alkaline solution, with optional heating, and with the addition of catalysts, such as powdered copper. The diazosulfides, formed as intermediates, need not be isolated. A nitro group in the 3-position of the compounds of Formula 1 can be converted into the NH -group, for example, in accordance with reduction methods set forth under (a). Preferably, the nitro group is catalytically hydrogenated e.g., on Pt or Pd), but it is also possible to reduce the nitro group with nascent hydrogen (Zn, Sn or Fe reacted with hydrochloric or sulfuric acid) or with Fe(OH) in ammonia.

A compound of Formula 1 can be converted into the associated acid addition salt with an acid in a conventional manner. For this reaction, those acids are suitable which yield physiologically compatible salts. Thus, organic and inorganic acids can be employed, such as, for example, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monoor polybasiccarboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malcic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methaneor ethanesulfonic acid, ethanedisulfonic acid, B-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalene-monoand -disulfonic acids, sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or phosphoric acids, such as orthophosphoric acid, etc.

Conversely, compounds of Formula 1 can be liberated from the acid addition salts thereof by treatment with strong bases, such as sodium or potassium hydroxide, sodium or potassium carbonate.

Finally, an aminophenylalkanol derivative of Formula I can be converted into the quaternary salt thereof by treatment with lower alkyl esters. For the preparation of such a quaternary compound, suitable materials include, but are not limited to: alkyl halides, such as methyl chloride, bromide or iodide, or ethyl chloride, bromide or iodide, or also dialkyl sulfates,

such as, for example, dimethyl or diethyl sulfate. The conditions for preparing a quaternary compound are conventional as described in the literature.

When the compounds of Formula 1 contain a center of asymmetry, they are usually present in the racemic form. If the compounds exhibit two or more centers of asymmetry, then they are obtained during the synthesis in general as mixtures of racemates, from which the individual racemates can be conventionally isolated and obtained in pure form, for example, by repeated recrystallization from suitable solvents. Such racemates can be separated into the optically opposite forms thereof in accordance with a number of conventional methods (ltSCl'lhtll in the literature.

Thus, it is possible to precipitate several racemic mixtures as cutetics instead of in the form of mixed solid solutions and separate then rapidly in this manner; in these cases, a selective precipitation can also be possible. However, it is preferred to employ chemical separation, wherein diastereomers are formed from the racemic mixture by reaction with an optically active separating agent. Thus, an optically active acid can, if desired, be esterified with an aminophenylalkanol of Formula 1. For example, salt diastereomers or ester diastereomers of the aminophenylalkanols of Formula 1 can be formed, if desired, with optically active acids, such as dand l-tartaric acid, dibenzoly-dand -l-tartaric acid, diacetyl-dand -l-tartaric acid, B-camphorsulfonic acid, dand lmandelic acid, dand l-malic acid or dand l-lactic acid. The difference in the solubility of the thus-obtained diastereomers permits the selective crystallization of one form and the regeneration of the respectively optically active substituted aminophenyla1 kanols from the mixture.

The optically opposite forms can also be separated biochemically with the use of selective enzymatic reactions. Thus, the racemic aminophenylalkanols can be exposed to an asymmetrical oxidase, which latter destroys one form by oxidation, whereas the other form remains unaltered. A hydrolase can be employed in connection with a derivative of the racemic mixture for the preferred formation of one form of the substituted aminophenylalkanols. Thus, esters of the aminophenylalkanols of Formula l can be subjected to the effect of a hydrolase which selectively saponifies one enantiomorph and leaves the other one unchanged.

Furthermore, it is, of course, possible to obtain optically active compounds in accordance with the methods described in paragraphs (a) through (j), by employing starting materials which are already optically active.

The compounds of Formula 1 and/or the physiologically acceptable metal and ammonium as well as acid addition salts thereof can be employed in a mixture with conventional pharmaceutical excipients. Carrier substances can be such organic or inorganic compounds suitable for parenteral, enteral or topical application and which, of course, do not deleteriously react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc.

For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Ampoules are convenient unit dosages.

For enteral application, particularly suitable are tablets or dragees which are also characterized by talc and/or a carbohydrate carrier or binder or the like, the carbohydrate carrier being preferably lactose and/or corn starch and/or potato starch. A syrup or the like can also be used wherein a sweetened vehicle is employed.

For topical application, viscous to semi-solid forms are used such as liniments, salves, or creams, which are, if desired, sterilized, or mixed with auxiliary agents, such as preservatives, stabilizers, or wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.

The compounds of this invention are preferably administered in dosages of 1-2.000 mg per dosage unit to animals, including, but not limited to, mammals and avians.

e.g., cattle, cats, dogs and poultry. Preferably, they are administered to mammals in a dosage of 1 to 100, particularly 10-50 mg per dosage unit, the mg/kg ratio being about 0.01 to 2 mg/kg. In pharmaceutical compositions, the carrier is usually present in an amount of 1-10,000 mg, preferably 10 to 5,000 mg. The dosages are preferably on a daily basis, in a single daily dose, but can be alternatively administered in divided doses.

Generally speaking, the compounds of Formula 1 are useful for the same indications as lbufenac and can be employed in the same manner.

The starting compounds for the production of the compounds of Formula 1 are, for the most part, either conventional or described in Belgian Pat. No. 718,242, corresponding to South African Patent application No. 68/471 1 and U.S. Patent application Ser. No. 746,326, or they can be simply prepared from said conventional or described compounds, by generally known chemical methods. Furthermore, starting materials can be obtained in accordance with the following processes:

1. By reacting the 4-nitrobromobenzes of Formula 18,

known from the literature or producible analogously thereto,

with amines of Formula 7, the compounds ZNO are obtained, which can be reduced to compounds ZNH By diazotization and Sandmeyer reaction, compounds Z-l-lal are obtained, and from these latter compounds, organometallic compounds of Formula 12 can be produced.

11. The 3-nitro-4-bromacetophenones of Formula 19, substantially known from the literature or producible analogously thereto,

are reacted with the amines of Formula 7 to form compounds of formula 20 The nitro group can be reduced to the amino group, and the latter can be exchanged against F, Hal, cn s or C l-1 S in accordance with the methods described in the foregoing. The keto group in 20 or in a secondary product prepared therefrom can be reduced to a secondary alcohol group, or can be converted, with an organometallic compound of Formula 2, into a tertiary alcohol of the formula ZCR (OH)- CH (21). Compounds of Formula 21 can be dehydrated, in accordance with conventional methods, to olefins of the formula ZCR CH (22), or can be converted into halogenides of the formula ZCR Hal-Cl-l (23). The olefins of Formula 22 can be converted into epoxides of the formula The last-mentioned halogen compounds can be converted into compounds of the formula ZCHR CH NH for example, by means of the Gabriel synthesis, which latter compounds serve as starting materials for the preparation of diazonium salts of Formula 10.

Examples of pertinent literature for the above processes include, but are not limited to: IR. Geigy A.G., Dutch Patent application No. 67/147213.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.

The following examples, the temperatures are in Centigrade. Usual working up operation means: water is added; the reaction mixture is, if desired, adjusted to the disclosed pH value by the addition of hydrochloric acid or solution of sodium hydroxide; the reaction mixture is extracted with ethyl acetate, chloroform or ether; dried over sodium sulfate; filtered; the solvent distilled off; and the residue is distilled or crystallized from the solvent set forth in connection with any particular reaction.

DMF means dimethyl formamide;

Diglyme means diethylene glycol dimethyl ether; and

THE means tetrahydrofuran.

EXAMPLE I a. 6.7 g. of a-(3-ch1or0-4-piperidinopheny1)-propionic acid is dissolved in 75 ml. of absolute THF and mixed with 3.5 ml. of triethylamine; at -10, a solution of 2.4 m1. of the ethyl ester of chloroformic acid in ml. of THF is added dropwise within 15 minutes. After stirring at l0 for 1/2 hour, 1.9 g. of NaBH, is introduced into the solution containing the mixed anhydride of monoethyl carbonate and the above-mentioned acid, 2-(3-ch1oro-4- piperidinophenyl)-4,6-dioxaoctane-3,S-dione. The reaction mixture is thereafter stirred at room temperature for 90 minutes. After adding 40 ml. of water, the mixture is extracted with ether, and the residue obtained after the ether has been removed by evaporation is boiled for onehalf hour with a solution of 1 g. of KOH in 30 ml. of ethanol. After the ethanol has been distilled 05 and the reaction mixture has been worked up as usual and chromatographed on A1 0 2-(3-ch1oro-4-piperidinopheny1)-propano1 is obtained, m.p. 5657 (hexane).

Analogously, the corresponding 4-piperidinoary1-alkano1s are obtained from:

2-(3-bromo-4-piperidinopheny1)-4,6-dioxa-octane-3,5-

dione 2-( 3-methy14piperidinopheny1)-4,6dioxa-octane-3,5-

dione 2-( 4-piperidinonaphthy1-1 )-4,6-dioxa-octane-3,5-dione. b. 5 g. of 2-(3-chloro-4 piperidinophenyl)-propanol is dissolved in 50 ml. of absolute benzene and mixed with 1.6 g. of KCNO. Subsequently, 3.1 ml of trifluoroacetic acid is gradually added. The reaction mixture is agitated for 15 hours at room temperature. The usual working-up operation yields 2-( 3-chloro-4-piperidinophenyl)-propyl carbamate having the boiling point of 185190/0.05 mm., and the melting point of 66-67 (diisopropyl ether).

EXAMPLE 2 a. A solution of 13.3 g. of a( 3-chloro-4-piperidino-pheny1)- propionic acid, m.p. lO5-106 in 80 ml. of absolute THF is added dropwise into a mixture of 2.84 g. of LiAll-l, in

m1. of absolute THF. The reaction mixture is boiled for 8 hours, 10 ml. ofwater in 15 m1.ofT1-1F,as well as 20 ml. of 25 percent solution of sodium hydroxide are added, the mixture is decanted, and the residue is washed with ether. After drying, filtration and concentration by evaporation of the combined organic phases, 2-( 3-ch1oro' 4-piperidinophenyl)-propanol is obtained, m.p. 5657. Analogously, by reduction with LiA1H and using the following compounds:

3-ch1oro-4-piperidinophenylacetic acid a-( 3-fluoro-4-piperidinophenyl )-propionic acid a-( 3-bromo-4-piperidinopheny1)-propionic acid a-( 3-iodo-4-piperidinophenyl )-propionic acid a-(3-amino-4-piperidinopheny1)propionic acid a-(3-methy1-4-piperidinopheny1)-propionic acid a-( 3-ethy1-4-piperidinophenyl)-propionic acid a-( 3methylmercapto-4-piperidinophenyl)-propionic acid a-( 3-ethy1mercapto-4-piperidinopheny1)-propi0nic acid (+)-a-( 3-chloro-4-piperidinophenyl)-propionic acid ()-a-( 3-chloro-4-piperidinopheny1)-propionic acid (+)-a-(3-bromo-4-piperidinopheny1)-propionic acid ()-a-(3-bromo4-piperidinopheny1)-propionic acid (+)-a-( 3-methyl-4-piperidinophenyl)-propionic acid ()-a-( 3-methy1-4-piperidinophenyl )-propionic acid (+)-a-( 3-ethylmercapto-4-piperidinophenyl )-propionic acid (-)-a-( 3-ethy1mercapto-4-piperidinophenyl)-propionic acid a-( 3-ch1oro-4-pyrro1idinophenyl)-propionic acid a-( 3-bromo-4-pyrro1idinopheny1)-propionic acid a-( 3-methyl-4-pyrro1idinophenyl)-propionic acid 04-( 3-amino-4-pyrro1idinopheny1)-propionic acid a-( 3-methylmercapto-4-pyrro1idinopheny1)-propionic acid a-( 3-ethylmercapto-4-pyrrolidinophenyl)-propionic acid a-( 3-ch1oro-4-homopiperidinophenyl )-propionic acid a-( 3-bromo-4-homopiperidinophenyl )-propionic acid a-( 3-ethy1mercapto-4-homopiperidinophenyl )-propionic acid a-( 3-ch1oro-4-piperidinopheny1)-butyric acid a-( 3-bromo-4-piperidinophenyl )-butyric acid a-( 3-methy1-4-piperidinophenyl)-butyric acid a-( 3ethylmercapto-4-piperidinophenyl )-butyric acid 4-piperidinonaphthy1-1-acetic acid a-(4-piperidinonaphthyl1 )-propionic acid a-(4-pyrrolidinonaphthyl- 1 )-propionic acid a-( 4-homopiperidinonaphthyl-1 )-propionic acid a-( 3-methyl-4-piperidinonaphthyl-1 )-propionic acid a-( 3-ch1oro-4-piperidinonaphthyl-1 )-propionic acid (+)-a-(4-piperidinonaphthy1-l )-propionic acid (-)-a(4-piperidinonaphthy1-1 )-propionic acid the compounds set forth below are produced:

2-( 3-ch1oro-4-piperidinophenyl )-ethanol, b.p. l35-l 3 8 2-( 3fluoro-4-piperidinophenyl )propano1, b.p. 133-134 /0.05 mm. 2-(3-bromo-4-piperidinopheny1)-propanol, m.p. 55

2-(3-iodo-4-piperidinopheny1)-propano1, b.p. 200-208 /0.05 mm. 2-( 3-amino-4-piperidinophenyl )-propano1, m.p. 78-79 2-( 3-ethylmercapto-4-pyrrolidinophenyl)-propanol, b.p.

170-l 72/0.05 mm.

2-( 3-chloro-4-homopiperidinophenyl )-propanol, b.p.

l75179/0.05 mm.

2-( 3-bromo-4-h0mopiperidinophenyl )-propanol, b.p.

200-206/0.01 mm. 2-( 3-ethylmercapto-4-homopiperidinophenyl )-prpanol,

2-( 3-chloro-4-piperidinophenyl)-butanol, b.p. l73-l77 2-( 3-bromo-4-piperidinophenyl)-butanol, b.p. l98-201 2-( 3methyl-4-piperidinophenyl)-butanol, b.p. l46l50 the corresponding alcohols:

2-( 3bromo-4-piperidinophenyl )-propyl acetate, b.p.

l75-l 80/0.0l mm. 2-( 3-methyl-4-piperidinophenyl )-propyl acetate, b.p.

2-( 3-methylmercapto-4-piperidinophenyl )-propyl acetate,

b.p. 166-l70/0.0l mm.

2-(3-ethylmercapto-4-piperidinophenyl)-propyl b.p. l85-l90/0.0l mm.

2-(4-piperidinonaphthyl-l)-ethyl acetate, hydrochloride,

m.p. 169-l7l 2-(4-piperidinonaphthyl-l )-propyl acetate, b.p. l65l67 /0.0l mm.

2-( 3-chloro-4-piperidinophenyl )-propyl l38/0.05 mm.

2-(4-piperidinonaphthyl-l)-ethyl benzoate, b.p. 225/0.0l

2-( 3-chloro-4-piperidinophenyl)-propyl benzoate b.p.

l65l70/0.01 mm.

c. At 0 and under agitation, 5 g. of 2-( 3-chloro-4- piperidinophenyl)-propanol in 20 ml. of DMF is gradually added to a suspension of 4.8 g. of NaH in 50 ml. of DMF. The reaction mixture is stirred for 20 minutes; thereafter, 4.2 g. of CH in ml. of DMF is added dropwise, and the reaction mixture is agitated overnight at room tempcruturc. The mixture is then worked up as usual, thus obtaining 2-(3-chloro-4-piperidinophenyl)-propylmethy| ether, b.p. l35l0.05 mm.

acetate,

butyrate, b.p.

Analogously, the following compounds are obtained from the corresponding alcohols, with methyl iodide:

2-(3-bromo-4-piperidinophenyl)-propylmethyl ether, b.p.

l60- l 63/0.02 mm.

2-(3-methyl-4-piperidinophenyl)-propylmethyl ether, b.p.

l l8l l9/0.0l mm.

2-(3-ethylmercapto-4-piperidinophenyl)-propylmethyl ether, b.p. l83187/0.0l mm.

2-( 4-piperidinonaphthyll )-propylmethyl l50-l60/0.0l mm.;

ether, b.p.

with ethyl iodide:

2-(B-ethylmercapto-4-piperidinophenyl)-propylethyl ether,

b.p. 200208/0.0l mm.

2-(4-piperidinonaphthyl-l )-propylethyl ether, b.p. l7l-I7 with propyl iodide:

2-(3-chloro-4-piperidinophenyl)-propylpropyl ether, b.p.

l49l52/0.0l mm.

2-( 4-piperidinonaphthyl-l )-propylpropyl l90200/0.0l mm.

ether, b.p.

with n-butyl bromide:

2-( 4-piperidinonaphthyl-l )-propyl-n-butyl 2082 l 5/0.0l mm,

ether, b.p.

with benzyl chloride:

2-(3-chloro-4-piperidino henyl)-propylbenzyl ether, b.p.

with ally] bromide:

2-( 3-chloro-4-piperidinophenyl )-propylallyl ether, b.p.

with 2-hydroxyethyl bromide:

2-( 3-chloro-4-piperidinophenyl )-propyl-2 '-hydroxyethyl ether, b.p. l90l95/0.005 mm.

with 2-methoxyethyl bromide:

the methyl and ethyl esters, respectively, of the corresponding acids, by reduction with LiAll'L:

2-( 3-chloro-4-piperidinophenyl)-propanol, m.p. 565 7 2-( 3-bromo-4-piperidinophenyl)-propanol, m.p. 55

2-(3-methyl-4-piperidinopheny1)-pr0panol, b.p. l26 l 28 /0.0l mm.

2-( 4-piperidinonaphthyl-l )-ethanol, m.p. 6062 b. At 0 and under agitation, 5.06 g. of 2-(3-chloro-4- piperidinophenyl)-propanol is added dropwise to a suspension of 4.8 g. of NaH in 50 ml. of absolute THF; the reaction mixture is stirred for another 20 minutes at 0, and then 5.7 g. of 3-chloro-4-piperidino-a-methyl-phenylacetyl chloride in I5 m]. of absolute THF is added dropwise, and the reaction mixture is agitated overnight at room temperature. Thereafter, the mixture is decanted, the residue washed with THF, and worked up as usual, obtaining in this manner a-(3-chloro-4-piperidinophenyl )-pr0p-ionic acid-[ 2-( 3-chloro-4-piperidinophen yl propyll-ester as a non-distillable oil.

Analogously, the following compounds are obtained from the corresponding alcohols by esterification with the corresponding acid chlorides or anhydrides:

2-( 3-chloro-4-piperidinophenyl )-propyl propionate, b.p.

l58l6l/0.0l mm.

2-( 3-bromo-4-piperidinophenyl )-propyl propionate, b.p.

ll/0 02 mm.

2-( 3-methyl-4-piperidinophenyl )-propyl propionate, b.p.

l24-l27/0.0l mm.

2-( 3-chloro-4-piperidinophcnyl tpropyl pulmitntc, b.p.

2-(3-chloro-4-piperidinophenyl)-propyl stearate, b.p.

250-253/0.0l mm. and the 2-(4-piperidinonaphthyl-l propyl ester of 3-chloro-4-piperidino-a-methylphenylacetic acid; non-distillable.

EXAMPLE 4 a. 14.1 g. of a-l3-chloro-4-(2-oxopiperidino)phenyl]- propionic acid (m.p. 66; obtainable by condensing a-(3- chloro-4-amino phenyl)-propionic acid methyl ester with m-bromovaleric acid chloride, cyclization of the amide with sodium ethylate to obtain the methyl ester of a-[3- chloro-4-(2-oxopiperidino)-phenyl]-propionic acid, and saponification with KOH in ethanol) is dissolved in 200 ml. of THF and added dropwise to a suspension of 9.5 g. of LiAll-I in 150 ml. of THF under stirring. The reaction mixture is boiled for 24 hours, ethyl acetate is added thereto, and the mixture is worked up in the usual manner, thus obtaining 2-(3-chloro-4-piperidinophenyl)- propanol, m.p. 5 6-5 7.

b. 5. g. of 2-(3-chloro-4-piperdinophenyl)-propanol is dissolved in 30 ml. of pyridine. At a solution of 3.8 g. of p-toluene-sulfonyl chloride in 10 ml. of pyridine is gradually added dropwise. The reaction mixture is stirred for 3 hours. The usual working-up operation results in 2- (3-chloro-4-piperidinophenyl )-propyl-p-toluenesulfonate, m.p. 8 l-82.

Analogously, 2-( 3-chloro-4-piperidinophenyl )-propylmethanesulfonate, m.p. 5052, is obtained by reaction with methanesulfonyl chloride.

EXAMPLE 18 ml. of a l-molar ether solution of LiAll-l, is added to a suspension of 10.7 g. of anhydrous AlCl in 50 ml. of absolute ether. Within one hour, there is added dropwise to this reaction mixture a solution of 4.6 g. of l-methyl-1-(3-methyl-4- piperidinophenyl)-ethylene oxide (obtainable from 3-methyl- 4-piperidinoacetophenone by reaction with CH MgBr to the secondary alcohol, splitting off water to form 3-methyl-4- piperidino-a-methylstyrene, reaction with N-bromosuccinimide in the aqueous phase to obtain the corresponding bromohydrin, and splitting off HBr with solution of sodium hydroxide) in 70 ml. of absolute ether. The reaction solution is boiled for 2 hours, hydrolyzed by the addition of 10 ml. of water and 100 ml. of 10 percent sulfuric acid and worked up as usual, thus obtaining 2-(3-methyl-4-piperidinophenyl)- propanol,b.p. l26l28/0.01 mm.

EXAMPLE 6 5.8 g. of a-(3-nitro-4-piperidinophenyl)-propionic acid hydrazide (obtainable by reacting a-( 3-nitro-4-piperidinophenyl)-propionic acid ethyl ester with hydrazine) is dissolved in 40 ml. lN hydrochloric acid. After a layer of 50 ml. of ethyl acetate has been poured on top of the reaction mixture, the latter is cooled to --l0; then, with thorough agitation, a solution of 1.4 g. of NaNO- in 3 ml. of water is added thereto. After minutes, the organic phase is separated, and the aqueous-acidic solution is neutralized with Na CQ, and once again extracted with ethyl acetate. The combined extracts, containing the thus-formed a-( 3-nitro-4-piperidinophenyl)- propionic acid azide, are cooled to and mixed dropwise, under stirring, with a solution of 0.8 g. of NaBl-L, in 10 ml. of methanol. After 15 minutes, cooling is discontinued, and the reaction mixture stirred for another 1.5 hours at room temperature. After the inorganic salts have been vacuum-filtered, the filtrate washed with water, dried and evaporated for concentrating purposes, 2-( 3-nitro-4-piperidinophenyl)-propanol is obtained, b.p. 175178/0.05 mm.

Analogously, the corresponding 2-aryl-propanols are obtained from the corresponding hydrazides by way of the following intermediates:

a-( 3-chloro-4-piperidinophenyl)-propionic acid azide a( 3-bromo-4-piperidinophenyl)-propionic acid azide a-( 3-methyl-4-piperidinophenyl )-propionic acid azide a-(4-piperidinonaphthyl-l )-propionic acid azide.

EXAMPLE 7 13 g. of a-(3-chloro4-piperidinophenyl)-propionaldehyde (obtainable by Wittig reaction of 3-chloro-4- piperidinoacetophenone with methoxymethyl-tn'phenylphosphonium chloride and subsequent hydrolysis of the vinyl ether, or by Rosenmund reduction of the corresponding acid chloride) is dissolved in 50 ml. of ethanol and added dropwise to a solution of 3 g. of NaBH, in 75 ml. of ethanol. The reaction mixture is stirred for 2 hours at room temperature and then worked up as usual, thus obtaining 2-( 3-chloro- 4-piperidinophenyl)-propanol, m.p. 5657.

EXAMPLE 8 7.5 g. of the ethyl ester of 3-methyl-4-piperidino-achlorophenyl-acetic acid (hydrochloride, m.p. l40-l42; obtainable from the ethyl ester of 3-methyl-4-piperidinomandelic acid with SOC] in CH Cl is dissolved in 70 ml. of absolute ether, and slowly added dropwise to a suspension of 2.2 g. of LiAll-L, in ml. of ether. The reaction mixture is boiled for several hours. Thereafter, methanol is added, and the reaction mixture worked up as usual, thus obtaining 2-( 3-methyl-4 -piperidinophenyl)-ethanol, b.p. llO1l5/0.0l mm.

Analogously, 2-( 3-methyl-4-piperidinophenyl )-propanol, b.p. l26l28/0.0l mm., is obtained from a-(3-methyl-4- piperidinophenyl)-a-chloropropionic acid ethyl ester (obtainable from the ethyl ester of 3-methyl-4-piperidino-amethylmandelic acid with SOCl by reduction with LiAll-l.,.

EXAMPLE 9 14.2 g. of a-(3-chloro-4-piperidinophenyl)-propionyl chloride (b.p. l44l46/0.05 mm.; obtainable from a-(3- chloroA-piperidinophenyl)-propionic acid and SOCI in benzene) is dissolved in ml. of ether and gradually added dropwise to a suspension of 2.0 g. of LiAlH. in 100 ml. of ether. The reaction mixture is stirred for 4 hours at room temperature, then mixed with methanol and thereafter with 15 percent aqueous solution of sodium hydroxide, and worked up as usual, thus obtaining 2-(3-chloro-4-piperidinophenyl)- propanol, m.p. 5657.

EXAMPLE 10 12.8 g. of the butyl ester of a-(3-chloro-4-piperidinophenyl)-propionic acid is dissolved in a mixture of 100 ml. of THF and 50 ml. of diglyme and added dropwise to a solution of 3.8 g. of NaBl-L, and 14 g. of boron trifluoride etherate in 100 ml. of Tl-lF/diglyme, cooled to 0. The reaction mixture is stirred for 1 hour at 0, then heated for 45 minutes to 60, mixed with water, worked up as usual, and there is thus produced the 2- (3-chloro-4-piperidinophenyl)-propylbutyl ether, b.p. l57-161/0.0l mm.

Analogously, the following compounds are obtained by reducing the corresponding ethyl ester or isopropyl ester:

2-(3-chloro-4-piperidinophenyl)-propylethyl ether, b.p.

l35-137/0.03 mm. 2-( 3-chloro-4-piperidinophenyl )-propylisopropyl b.p. l38-142/0.03 mm.

EXAMPLE 11 7.5 g. of 2-(3-methyl-4-piperidinophenyl)-propen-l -ylmethyl ether (obtainable from 3-methyl-4- piperidinoacetophenone and methoxy-methyl-triphenylphosphonium chloride) is dissolved in 100 ml. of methanol and then hydrogenated on 5% Pd/C until the absorption of hydrogen is terminated. The catalyst is filtered off, the reaction mixture concentrated by evaporation, and thus the 2-(3- methyl-4-piperidinophenyl)-propylmethyl ether is produced, having the boiling point of l l8l l9/0.0l mm.

Analogously, by reacting other substituted acetophenones or acetonaphthones with methoxymethylor phenoxymethyltriphenylphosphonium chlorides, further vinylmethyl or vinylphenyl ethers are obtained which are then converted into the corresponding ethers by means of reduction.

EXAMPLE l2 12 g. of 2-(3-methyl-4piperidinophenyl)-allylmethyl ether (obtainable by reacting 3-methyl-4-piperidino-urmethoxyacetophenone with CH MgBr and subsequent splitting off of water with polyphosphoric acid, or by reacting 3-methyl-4- piperidino-w-methoxyacetophenone with triphenylether,

methylphosphonium bromide) is dissolved in 100 ml. of ethanol and hydrogenated with Pd/C until the absorption of hydrogen is terminated. The reaction mixture is filtered and then concentrated by evaporation, thus obtaining 2-( 3- methyl-4-piperidinophenyl)-propylmethyl ether, hp. 1 18-1 1 9/0.01 mm.

EXAMPLE 13 15.4 g. of the ethyl ester of a-(4-piperidinonaphthyl-l)- acrylic acid, m.p. 63-65, is boiled together with 2 g. of Li- AlH, in 200 ml. of absolute THF for 15 hours. Thereafter, the reaction solution is mixed with ml. of NaOH solution, the THF phase is decanted and thus removed, the residue is washed twice with ether, and the combined organic phases are dried and concentrated by evaporation. The residue is dissolved in 200 ml. of absolute THF, and then 2 g. of LiAll-l, is added and the reaction mixture boiled once more, for 8 hours. The mixture is worked up as usual, thus obtaining 2-(4- piperidinonaphthyl-l )-propanol, m.p. 67"69.

Analogously, with LiAll-hfrom ethyl a-(3-ch1oro-4-piperidinophenyl)-acrylate ethyl a-( 3-bromo-4-piperidinophenyl )-acrylate ethyl a-( 3-methyl-4-piperidinophenyl )-acrylate and ethyl a-(4-piperidinonaphthyl-1)-crotonate, respectively,

the following compounds are obtained:

2-(3-chloro-4-piperidinophenyl)-propanol, m.p. 565 7 2-( 3-bromo-4-piperidinophenyl )-propanol, m.p. 55

2-(3-methyl-4-piperidinophenyl)-propanol, b.p. 126128 /0.01 mm., and 2-(4-piperidinonaphthyl-l )-butanol, m.p. 6869.

EXAMPLE l4 9 g. of l-(4-piperidinonaphthyl-l )-ethane-l,2-diol (ob tainable by reducing the ethyl ester of 4-piperidinonaphthyl-1- glyoxylic acid with LiA1H is hydrogenated in methanol with CuCr O catalyst at 100 atmospheres and 140. After the catalyst has been filtered off and the mixture has been concentrated by evaporation, 2-(4-piperidinonaphthyl-l )-ethanol is obtained, b.p. l64168/0.01 mm. and m.p. 6062.

Analogously, 2-(4-piperidinonaphthyl-l)-propanol, m.p. 67-69, is obtained from 2-( 4-piperidinonaphthyl-1 propane-1,2-diol; and hydrogenation (in ethanol at 150 atmospheres and 160) of ethyl 2-(3-methyl-4-piperidinophenyl )-2-hydroxypropionate yields 2-( 3-methyl-4- piperidinophenyl )-propano1 [b.p. 126-l 28/0.01 mm. esterification with adamantane- 1 -carboxylic acid chloride/pyridine results in 2-(3-methyl-4-piperidino-phenyl)- propyI-(adamantane-l-carboxylate), m.p. 8788].

EXAMPLE l5 13 g. of 2-(3-acetyl-4-piperidinophenyl)-propylmethyl ether (obtainable by diazotization of 2-(3-amino-4- piperidinophenyl)-propylmethyl ether, reaction with CuCN to form the 2-( 3-cyano-4-piperidino-phenyl)-propylmethyl ether and reaction with CH MgI) is heated in 100 ml. of diethylene glycol, together with 6 g. of KOH and 10 ml. of 85 percent hydrazine for 1 hour at 100 C. Thereafter, the temperature is slowly increased until the hydrazone is decomposed, the excess of the hydrazine and the formed water being removed by evaporation. The reaction mixture is boiled for another 4 hours, and then worked up as usual, obtaining 2-( 3-ethyl-4- piperidinophenyl)-propylmethyl ether, b.p. 130-l32/0.05

mrn.

EXAMPLE 16 9.3 g. of 2-(3-ch1oro-4-aminophenyl)-propanol is dissolved in 150 ml. of ethyl acetate, mixed with 4.3 g. of freshly distilled succinic dialdehyde and immediately hydrogenated at 50 on PtO After the hydrogen absorption is terminated and the reaction mixture has been worked up as usual, 2-( 3- chloro-4-pyrro1idinophenyl)-propanol is obtained, b.p. l28-l30/0.01 mm.

Analogously, it is also possible to cyclize 2-[3-chloro-4-(3- formylpropylamino)-phenyl]-propanol, obtained in situ by reacting 4-bromobutyraldehyde-dimethyl acetal with 2-(3- chloro-4-aminopheny)-propanol and splitting the acetal group with HCl, under hydrogenating conditions to produce 2-(3- chloro-4-pyrrolidinophenyl)-propan0l.

EXAMPLE 1? 14.5 g. of a-(4-piperidinonaphthyl-l )-acryloyl chloride (obtainable from a-(4-piperidinonaphthyl-l)-acrylic acid (m.p. 179-181) with SOC1 in benzene) is added dropwise, at room temperature, to a suspension of 2 g. of LiAll-l, in 150 ml. of ether. The reaction mixture is stirred for several hours at room temperature; then, methanol is added, and the reaction mixture worked up as usual, obtaining 2-(4- piperidinonaphthyl-l )-propanol, m.p. 6769.

EXAMPLE 18 13.4 g. of crude 2-[3-methyl-4-(2-hydroxypiperidinoJ- phenyl]-propanol (obtainable by condensing 11.5 g. of wbromovaleraldehyde dimethyl acetal with 8.5 g. of 2-( 3- methyl-4-aminophenyl)-propanol in benzene with the addition of 7 g. of K CO and subsequent splitting of the acetal group with aqueous-methanolic HCl solution) is hydrogenated in 150 ml. of ethanol, with the addition of 0.5 g. of ptoluenesulfonic acid at 50 on 2.5 g. of PtO- obtaining 2-(3- methyl-4-piperidinophenyl )-propanol, b.p. 126-- 1 28/0.0 1

EXAMPLE 19 5.5 g. of 2-chloro-2-(3-methyl-4-piperidinophenyl)-ethylmethyl ether (obtainable by bromination of 3-methyl-4- piperidinoacetophenone to m-bromo-3-methyl-4- piperidinoaceto-phenone, reaction with sodium methylate to the methyl ether, reduction of the carbonyl group with N'aBH to the corresponding alcohol, and reaction with aqueous l-lCl) is boiled in 50 ml. of absolute ether with 0.3 g. of Li under a nitrogen atmosphere for 2 hours. To the thus-produced suspension, 3.1 g. of CH I in 10 m1. of ether is added; then, the reaction mixture is boiled for another hour and worked up as usual, thus obtaining 2-( 3-methy1-4-piperidinophenyl)-propylmethyl ether, hp. 1 l8l 19/0.01 mm.

EXAMPLE 20 6.55 g. of 2-chloro-2-(3-methyl-4-piperidinophenyl)-ethylmethyl ether is dissolved in 30 ml. of absolute THF. At 20 and under N 15 ml. of an approximately 2-molar CH Li-solution in ether is added dropwise and gradually to this solution. The reaction mixture is stirred for 1 hour at -20"; then, moist ether is added and the mixture is worked up as usual, thus obtaining 2-( 3-rnethyl-4-piperidinophenyl)-propylmethyl ether, b.p. 118-1l9/0.01 mm.

EXAMPLE 21 a. 52 g. of 2-( 3-nitro-4-bromophenyl)-propanol (obtainable by Friedel-Crafts reaction of bromobenzene with allyl a1- cohol, esterification of the thus-produced 2-pbromophenyl-propanol with acetic anhydride, nitration and saponification of the 2-( 3-nitro-4-bromophenyl)- propyl acetate) and 34 g. of piperidine are boiled in 300 ml. of benzene for 40 hours under a nitrogen atmosphere. After cooling, the reaction mixture is extracted with dilute hydrochloric acid, and the aqueous-acidic extract is made alkaline by means of solution of sodium hydroxide. Separation by chromatography on silica gel with benzene/methanol 9:1 results in 2-(3-nitro-4- piperidinophenyl)-propanol.

b. 25 g. of 2-(3-nitro-4-piperidinophenyl)-propanol is dissolved in 250 ml. of absolute ethanol and hydrogenated on Pd until the theoretical amount of hydrogen has been absorbed. The reaction mixture is filtered off, concentrated by evaporation, and the resultant product is 2-( 3- amino-4-piperidinophenyl)-propanol, b.p. l58-l60/0.l mm.; m.p. 7879.

Analogously, the ethers and esters of the nitro compound can be reduced to the amino compounds.

c. 1 1.5 g. of 2-( 3-arnino-4-piperidinophenyl)-propanol is dissolved in 50 ml. of water and 30 ml. of concentrated hydrochloric acid, and diazonium salt solution is gradually poured into a solution of Cu- Cl (produced by reducing 12 g. of copper sulfate and 10 g. of NaCl in 80 ml. of water with S0 The reaction mixture is heated for 30 minutes on a steam bath, and then worked up as usual, thus obtaining 2-( 3-chloro-4-piperidinophenyl propanol, m.p. 565 7.

d. 23 g. of 2-(3-amino-4-piperidinophenyl)-propanol is diazotized at 3-6 in a mixture of 35 m1. of concentrated hydrochloric acid and 100 ml. of water with a solution of 7.5 g. of NaNO in m1. of water. This diazonium salt solution is added, at room temperature, to a solution of 100 ml. of Cu Br (produced by reducing a solution of copper sulfate/NaBr with NaHSO then, the reaction mixture is heated for 45 minutes on a steam bath. The mixture is thereafter cooled off and worked up as usual, obtaining 2-( 3-bromo-4-piperidinophenyl )-propanol m.p. 55.

e. 28.5 g. of 2-(3-amino-4piperidinopheny1)-propanol is dissolved in 200 ml. of 15 percent hydrochloric acid and diazotized at 0 with 9 g. of NaNO in ml. of water. Subsequently, 22 g. of 40 percent tetrafluoboric acid is gradually added thereto. Under cooling, the reaction mixture is bufiered to a pH of 3-7, the diazonium tetrafluoborate is vacuum-filtered, washed with water, dried, and carefully heated to 150-160 until the termination of gas evolution. The residue is treated with dilute solution of sodium hydroxide, filtered, and worked up as usual, thus producing 2-(3-fluoro-4- piperidinophenyl)-propanol, b.p. 145150/0.01 mm.

f. 1 1.5 g. of 2-( 3-amino-4-piperidinophenyl)-propano1 is dissolved in 60 ml. of 18 percent sulfuric acid and diazotized at 04 with 4 g. of NaNO in 12 ml. of water. The thus-obtained solution is introduced under stirring into a mixture of 12.5 g. of K1 in ml. of 1N H 50 The reaction mixture is stirred for 18 hours at room temperature, heated until the evolution of nitrogen is terminated (about 20 minutes) on a steam bath, worked up as usual, and the product resulting therefrom is 2-(3-iodo-4- piperidinophenyl)-propanol, b.p. l45/0.01 mm.

. 23 g. of 2-( 3-amino-4-piperidinophenyl)-propanol is dissolved in 80 ml. of 12 percent of hydrochloric acid, cooled to 05, and diazotized by the addition of 7.2 g. of NaNO in 20 ml. of water. The thus-obtained solution is gradually allowed to drop underneath the surface of a solution of 6 g. of CH SH in 80 ml. of 20% of NaOH, at 70 and under agitation. Thereafter, the reaction mixture is heated to 90 until the evolution of nitrogen is terminated, then cooled, and acidified to a pH of 6 by means of hydrochloric acid. The reaction mixture is worked up as usual, thus obtaining 2-( 3-methylmercapto-4- piperidinophenyl)-propanol, b.p. 168170/0.01 mm.

EXAMPLE 22 A solution of 24 g. of NaOH in 100 ml. of water is added dropwise, under stirring, to a boiling mixture of 18.5 g. of 2- (3-chloro-4-aminophenyl)-propanol (m.p. l57-159; ob-

tainable by acetylation of 2-phenyl-propanol, nitration to 2- (4-nitrophenyl)-propyl acetate (b.p. 136/0.05 mm.),

hydrogenation to 2-(4-aminopheny1)-propyl acetate (b.p. 138/0.05 mm. acetylation to 2-(4-acetamidopheny1)-propyl acetate (m.p. 8990), chlorination with chlorine in glacial acetic acid to 2-(3-ch1oro-4-acetamidophenyl)-propyl acetate (m.p. 100-102) and hydrolysis) and 48 g. of 1,5-

dibromopentane in 150 ml. of water. The reaction mixture is boiled for another 3 hours, extracted with ether and worked up in the usual manner, obtaining 2-( 3-ch1oro-4- piperidinophenyl)-propanol, m.p. 565 7.

EXAMPLE 23 a. 7.4 g. of 2-(4-piperidinopheny1)-propyl-p-nitrobenzoate (obtainable by reacting 2-(4-aminophenyl)-propanol with 1,5-dich1oropentane and subsequent esterification with p-nitrobenzoyl chloride) is dissolved in 50 ml. of dioxane. To this solution, 0.5 g. of AlCl is added and thereafter, under stirring and at room temperature, a solution of 1.5 g. of chlorine in ml. of dioxane is added dropwise thereto. The reaction solution is additionally agitated for 3 hours at room temperature; then, the solvent is removed, the reaction mixture worked up as usual, the crude product is chromatographed on A1 0 and 2- 3-ch1oro-4 piperidinophenyl )-propyl-pnitrobenzoate is obtained in the fon'n of a yellow oil.

b. 1 g. of 2-( 3-chloro-4-piperidin0pheny1)-propyl-pnitrobenzoate is boiled with 15 ml. of ethanol and 2 m1. of 25% NaOH for 3 hours. The reaction mixture is worked up as usual, and the product is 2-( 3-chloro-4- piperidinophenyl)-propanol, m.p. 56-5 7.

EXAMPLE 24 25.6 g. of 2-(4-piperidinopheny1)-propy1methyl ether (obtainable by reacting 2-(4-aminopheny1)-propylmethyl ether with 1,5-dibromopentane) is dissolved in 150 ml. of dioxane and, after the addition of 0.5 g. of powdered iron, is mixed at room temperature, under stirring, dropwise with 18 g. of bromine in 50 ml. of dioxane. The mixture is stirred for another 3 hours at room temperature, and then the solvent is removed and the reaction mixture worked up as usual, thus obtaining 2-( 3-bromo-4-piperidinophenyl )-propylmethyl ether, b.p. 142145/0.01 mm.

EXAMPLE 25 15.6 g. of 2-(4-piperidinophenyl)-propyl acetate (obtainable by reacting 2-(4-aminophenyl)-propano1 with 1,5-

dibromopentane in butanol in the presence of K CO and subsequent acetylation) is added dropwise under vigorous stirring at 0 to a solution of 18 ml. of 65% HNO and 20 ml. of concentrated H SO -acid. The reaction mixture is stirred at room temperature for 1 hour and then poured on ice. The usual working-up operation yields 2-(3-nitro-4-piperidinophenyl)- propyl acetate, b.p. 180l850.01 mm.

EXAMPLE 26 8.2 g. of 2-(3-methylpheny1)-propylmethyl other is gradually mixed, at 20, in ml. of nitrobenzene, with the addition of 20 ml. of o-dichlorobenzene and 13.5 g. of anhydrous A1Cl with 6.5 g. of N-chloropiperidine. The reaction mixture is stirred for 3 hours and then decomposed with dilute hydrochloric acid. After the usual working-up operation, the product obtained is 2-(3-methyl-4-piperidinophenyl)-propy1- methyl ether, b.p. 118119/0.01 mm. EXAMPLE 27 a. 23.4 g. of 2-(3-arnino-4-piperidinophenyl)-propano1 is dissolved in ml. of 10 percent hydrochloric acid, and diazotized by the addition of 7.5 g. of NaNO in 20 ml. of water at O4. The thus-obtained solution is gradually added dropwise and under stirring to a solution of 16 g. of potassium ethylxanthogenate in 100 ml. of water, heated to 45. After the evolution of nitrogen is terminated, the reaction mixture is cooled and the pH adjusted to 6. The reaction product is filtered off, dissolved in about 200 ml. of 4N solution of sodium hydroxide, and then boiled for 1 hour under a nitrogen atmosphere. Thereafter, the reaction mixture is cooled, acidified to a pH of 5-6, worked up as usual, and the reaction product thus obtained is 2- (3-mercapto-4-piperidinophenyl )-propanol, b.p. 180/0.05 mm.

b. 2.5 g. of 2-(3-mercapto-4-piperidinopheny1)-propano1 is dissolved in 25 ml. of 1N sodium hydroxide solution and mixed batch-wise with 2.6 g. of dimethyl sulfate under a nitrogen atmosphere. The reaction mixture is then stirred for one-half hour at room temperature, mixed with 10 ml. of 2N NaOH, boiled under agitation for one-half hour, cooled to O10, acidified to a pH of 6-7 and worked up as usual, thus producing 2-(3-methylmercapto-4- piperidinophenyl)-propanol, b.p. 168170/0.01 mm.

. A solution of 13.2 g. of 2-( 3-mercapto-4-piperidinophenyl)-propy1methyl ether in 80 ml. of absolute THF is cooled to 0 and mixed with 2.5 g. of NaH. The reaction mixture is agitated for 1 hour at room temperature; then, 7.2 g. ofCH l in 20 ml. ofTHF is added dropwise, and the mixture is stirred for another 2 hours at room temperature and thereafter worked up as usual, obtaining 2-(2- methyl-mercapto-4-piperidinophenyl)-propylmethyl ether, b.p. l55l58/0.05 mm.

EXAMPLE 28 5.8 g. of 2-(4-piperidino-5,6,7,8-tetrahydronaphthyL1 propylmethyl ether (obtainable from l-piperidino-5,6,7,ll-

tetrahydronaphthalene by FriedeLCrafu; reaction with acetyl chloride to 4-piperidino-5,6,7,8-tetrahydroacetonaphthone,

Wittig reaction with methoxymethyl-triphenylphosphonium chloride and subsequent hydrogenation of the methoxymethylene compound) is boiled for 60 hours in 75 ml. of toluene with 9.5 g. of chloranil. Subsequently, the reaction mixture is concentrated by evaporation and made alkaline with NaOH. The usual working up operation yields 2-(4- piperidinonaphthyl-l)-propylmethyl ether, b.p. 15016O /0.0l mm.

EXAMPLE 29 24 g. of 3-chloro-4-piperidino-a-methylstyrene (obtainable by reacting 3-chloro-4-piperidinoacetophenone with cH Mgl,

hydrolysis and splitting off water) is dissolved in 50 ml. of 1 diglyme and mixed with 30 ml. of a l-molar solution of NaBl-l in diglyme. To this solution is gradually added dropwise, under stirring and with the introduction of N a solution of 5.6 g. of freshly distilled BF etherate in 12 ml. of diglyme; this is done within 30 minutes. The reaction mixture is mixed with 7 ml. of

water, and then 14 ml. of a 3N NaOH solution, as well as 14 ml. of 30% H are added dropwise at 80-l00. The reaction mixture is mixed with ice water, worked up as usual, and 2-(3-chloro-4-piperidinophenyl)-propanol is obtained, m.p. 5657.

EXAMPLE 30 29.6 g. of 2-( 3-methyl-4-piperidinophenyl)-propyl bromide is reacted with 2.6 g. of Mg-fillings in 100 ml. of ether. The reaction mixture is then cooled to oxygen is introduced for 4 hours, and the reaction solution is mixed with aqueous Nl-l Cl solution. The usual working up operation yields 2-(3- methyl-4-piperidinophenyl)-propanol, b.p. l26-128/0.0l

EXAMPLE 31 5 g. of 2-( 3-chloro-4-piperidinophenyl)-propylamine (obtainable from a-( 3-chloro-4-piperidinophenyl)-propionamide with LiAlH is dissolved in 100 ml. of percent aqueous acetic acid, and mixed under ice cooling with a solution of 2 g. of NaNO in 10 ml. of water. The reaction mixture is heated for 1 hour to 80, worked up as usual, and the basic reaction products are chromatographed on silica gel with benzenemethanol :1, thus obtaining 2-(3-chloro-4-piperidinophenyl)-propanol, m.p. 56-5 7'.

EXAMPLE 32 11.7 g. of 2-( 3-chlor04piperidinophenyl)-pr0pyl bromide (obtainable by nitration of 2-(4-br0mophenyl)-propyl bromide, reaction with 1 mol of piperidine, catalytic hydrogenation to 2-(3-amino-4-piperidinophenyl)-propyl bromide, diazotization and reaction with Cu Cl is dissolved in 50 ml. of DMF. 10 g. of anhydrous potassium acetate is added thereto, and the reaction mixture is agitated for 3 hours at 60. The usual working-up operation yields 2-(3-chloro-4- piperidinophenyl)-propyl acetate, b.p. l35-l 36/0.0l mm.; additionally, a small amount of 3-chloro-4-piperidino-amethylstyrene is produced.

Analogously, from 2-(3-methyl-4-piperidinophenyl)-propyl bromide (obtainable by Friedel-Crafts reaction of 2-piperidinotoluene with allyl bromide) by reaction with potassium acetate, 2-( 3-methyl-4-piperidinophenyl)-propyl tained, b.p. l2l/0.0l mm.

EXAMPLE 33 a. 14 g. of 2-(3-methyl 4-piperidin0phenyl)-propyl bromide is dissolved in 50 ml. of absolute DMF, and added dropwise at 0 to a suspension of 6 g. of benzyl alcohol and 2 g. of NaI-l in ml. of absolute DMF. The reaction mixture is stirred for 24 hours at room temperature and worked up as usual. The product obtained thereby is 2-( 3-methyl- 4-piperidinophenyl)-propylbenzyl ether, b.p. l6817l /0.05 mm.

16.5 of 2-(3-methyl-4-piperidinophenyl)-propylbenzyl ether is dissolved in 150 ml. of methanol and hydrogenated at room temperature on 1.6 g. of 5% PdC catalyst until the absorption of hydrogen is terminated. The reaction product is filtered ofi', concentrated by acetate is obevaporation, and 2-(3-methyl-4-piperidinophenyl)- propanol is thus obtained, b.p. l26l 28/0.0l mm.

EXAMPLE 34 To a solution prepared from 1.3 g. of Mg-filings and 12.7 g. of Z-piperidino-5-bromotoluene (obtainable be reacting 2- amino-5-bromotoluene with 1,5-dibromopentane) in 35 ml. of absolute ether, a solution of 11 g. of 2-chloropropylmethyl ether in 40 ml. of absolute benzene is added, the ether is evaporated, and the residue is boiled for 12 hours. After decomposing with aqueous NH Cl solution and conducting the usual working-up operation, 2-( 3-methyl-4- piperidinophenyl)-propyl-methyl ether is obtained, b.p. 1 l8-l l9/0.0l mm.

EXAMPLE 35 Under stirring and cooling to 0 a solution of 4 g. of ethylene oxide in 4 ml. of absolute ether is added to a Grignard solution of 1.7 g. of Mg-filings and 17.5 g. of 2- piperidino-S-bromotoluene in 40 ml. of absolute ether; the reaction mixture is allowed to stand overnight. Then, 40 ml. of benzene is added, the ether is distilled off, and the benzenic solution is boiled for 1 hour. After decomposing with aqueous NH, Cl solution and the usual working up operation, 2-(3- methyl-4-piperidinophenyl)-ethanol is obtained, b.p. 1 l5l l 6l0.0l mm.

EXAMPLE 36 14.1 g. of l-(3-methyl-4-piperidinophenyl)-ethyl bromide (obtainable by Friedel-Crafts reaction of 2-piperidinotoluene with acetyl chloride, reduction with NaBl-l, and subsequent reaction with aqueous HBr solution) is made to react in ml. of absolute ether together with 1.3 g. of Mg-filings. A solution of 4 g. of chloromethylmethyl ether in 50 ml. of absolute ether is gradually added dropwise to the Grignard solution. The reaction mixture is boiled for 2 hours and then worked up as usual after the addition of aqueous Nl-l Cl solution. The product thus obtained is 2-(3-methyl-4-piperidino-phenyl)- propylmethyl ether, b.p. l l8-l 19/0.0l mm.

EXAMPLE 37 To a solution of 19.5 of 2-piperidinochlorobenzene in 200 ml. of trichloroethylene, 14 g. of powdered anhydrous AlCl is added, and under cooling to below +5, 7 g. of allyl alcohol in 20 ml. of trichloroethylene is added dropwise thereto. The reaction mixture is allowed to assume room temperature, additionally stirred for 12 hours, decomposed by the addition of ice, and worked up as usual (pH 9), thus producing 2-(3- chloro-4-piperidinophenyl)-propanol, m.p. 56-5 7.

EXAMPLE 38 To a solution of 17.5 g. of 2-piperidinotoluene in 200 ml. of nitrobenzene, 14 g. of powdered anhydrous AlCl is added, and at 2025, 10 g. of 2-chloropropanol is added dropwise to this mixture. The reaction solution is agitated overnight at room temperature, thereafter heated for 3 hours on a steam bath, and decomposed by the addition of ice. The nitrobenzene is driven off with steam. After conducting the usual working up operation (pH 9), 2-(3-methyl-4- piperidinophenyl)-propanol is obtained, b. p. 126-l28/0.0l

EXAMPLE 39 To a solution of 19.5 g. of Z-piperidinochlorobenzene in ml. of trichloroethylene, 14 g. of powdered anhydrous MCI; is added, and at 0-5, a solution of 6 g. of ethylene oxide in 50 ml. of trichloroethylene is added dropwise to this reaction mixture. The reaction solution is agitated for 12 hours at 5-20, decomposed by the addition of ice, and worked up as usual (pH 9), thus obtaining 2-(3-chloro-4- piperidinophenyl)-ethanol, b.p. l35-l38/0.05 mm.

The following examples illustrate typical, but not all-inclusive, pharmaceutical compositions of the novel compounds which can be prepared according to conventional methods:

lactose 100 mg potato starch 37 mg tale 2 mg magnesium stearate 1 mg Coated EXAMPLE B: Tablets:

Each tablet contains: 2-( 3-chloro-4-piperidino-phenyl)-propanol 30 mg lactose 100 mg wheat starch 23 mg talc 2 mg The coating 150 mg) is a conventional mixture of polyvinyl pyrrolidone, titanium dioxide, calcium carbonate, sugar, talc, and glycerol.

EXAMPLE C:

Solution for Injection:

A solution of 2 kg of 2-( 3chloro-4-piperidino-pheny])- propanol in 198 kg of sesame oil is prepared and filled into 2 m1 ampoules in such a manner that each arnpoule contains 20 mg of the active agent.

EXAMPLE D: Syrup A mixture of 2-( 3-chloro-4-piperidino-phenyl)-propanol 0.4 kg glycerol (twice distilled) 6.0 kg cane sugar 54.0 kg methyl-p-hydroxybenzoate 0.07kg npropyl-p-hydroxybenzoate 0.03kg ethanol 12.5 kg flavorings as desired is prepared and mixed with distilled water in such a manner that the volume of the entire preparation is 100 l. A dosage unit (5 ml) contains mg of active substance EXAMPLE E: Hard Gelatin Capsules: Each hard gelatine capsule is filled with a fine powder consisting of 2-( 3-chloro-4-piperidino-phenyl)-propanol mg lactose 180 mg talc 18 mg magnesium stearate 2 mg Instead of 2-(3-chloro-4-piperidino-phenyl)-propanol, other compounds covered by Formula 1 as well as their physiologically compatible acid addition salts can be incorporated into similar compositions.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

l. A member selected from the group consisting of a compound of the formula wherein R, is OH, saturated or unsaturated aliphatic, cyclouliphatic or aromatic hydrocarbon carbonyloxy of one to [8 carbon atoms, illkylsullonyloxy of one to six carbon atoms or hydrocarbon arylsulfonyloxy of six to 10 carbon atoms, or alkoxy of one to four carbon atoms,

R, is H, CH or C H,, R is H, F, Cl, Br, I, N0 NH CH C H,,, CH S, C H,,S, R and R, each represents H or together CH CH-CH= CH, O is pyrrolidino, piperidino or homopiperidino, with the provision that when R, and R each represent H, R, is other than H; a physiologically compatible acid addition salt thereof and a quarternary ammonium salt thereof.

2. A member as defined by claim 1 wherein R, is OH. 3. A member as defined by claim 1 wherein R is CH,,. 4. A member as defined by claim 1 wherein R, is H,Cl, Br, Chg, ch 5 or C H S with the provision that when R, and R each represents H, R, is other than H. 5. A member as defined by claim 1 wherein R and R each represents H.

6. A member as defined by claim 1 wherein R and R together represent CH CHCH CH.

7. A member as defined by claim 1 wherein Q represents piperidino.

8. A member as defined by claim 1 wherein R is Cl, Br, CH CH S or C H,S, and R, and R, represent Hv 9. A member as defined by claim 1 wherein R is H, and R and R represent together CH CHC H CH. 10. A member as defined by claim 1 wherein R is CH R is Cl, Br, CH CH S or C H S, R and R is H, and Q is piperidino. 11. A member as defined by claim 1 wherein R, is CH R is H, R and R together represent CH CHCH CH,

and Q represents piperidino. 12; A member as defined by claim 1 wherein R, is OH, R, is Cl, Br, CH CH S or C H S, and R, and R, are H. 13. A member as defined by claim I wherein R, is OH, R, is H, and R and R together represent CH CHCH CH-. 14. A member as defined by claim 1 wherein R, is OH, R is CH R is Cl, Br, Cl-L,, CH S or C-,H,S, R, and R, represent H, and Q is piperidino. 15. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-chloro-4-piperidinophenyl )-ethanol, 2-( 3fluoro-4-piperidinophenyl )-propanol, 2-( 3chloro-4-piperidinophenyl )-propanol, 2-( 3-bromo4-piperidinophenyl )-propanol, 2-( 3-iodo-4-piperidinophenyl )-propanol, 2-( 3-nitro-4-piperidinophenyl )-propa.nol, 2-( 3arnin0-4-piperidinophenyl )-propanol 2-( 3-methyl-4-piperidinophenyl )-propanol, 2-( 3-ethyl-4-piperidinophenyl )-propan0l, 2-( 3methylmercapto Lpiperidinophenyl )-propanol. 16. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-ethylmercapto-4piperidinophenyl )-propanol, (+)-2-( 3chloro-4-piperidinophenyl )-propanol, ()-2-( 3chloro-4-piperidinophenyl )-propanol, (+)-2-( 3 -bromo-4-piperidinophenyl )-propan0l, ()-2-( 3bromo-4-piperidinophenyl )-propanol, (+)-2-( 3methyl-4-piperidinophenyl )propanol ()-2-( 3-methyl-4-piperidinophenyl)-propanol,

(+)-2-( 3-ethylmercapto-4-piperidinopheny1)-propanol,

( )-2-( 3-ethylmercapto-4-piperidinophenyl )-propanol,

2-( 3-chloro-4-pyrrolidinophenyl)-propanol.

17. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-bromo-4-pyrrolidino0henyl )-propanol,

2-( 3-methyl-4-pyrrolidinophenyl )-propanol,

2-( 3-arnino-4-pyrrolidinophenyl)-propanol,

2-( 3-methylme rcapto-4-pyrrolidinophenyl )-propanol 2-( 3-ethylmercapto-4-pyrrolidinophenyl)-propanol,

2-( 3-chloro-4-homopiperidinophenyl )-propanol 2-( 3-bromo-4-homopiperidinophenyl )-propanol,

2-( 3-ethylmercapto-4-homopiperidinophenyl)-propanol,

2-( 3-chloro4-piperidinophenyl )-butanol,

2-( 3-bromo-4-piperidinophenyl )-butanol.

18. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-methyl-4-piperidinophenyl )-butanol,

2-( 3-ethylmercapto-4-piperidinophenyl )-butanol,

2-( 4-piperidinonaphthyl-l )-ethanol,

2-(4-piperidinonaphthyl-l )-propanol,

2-( 4-pyrrolidinonaphthyl-l )-propanol,

2-( 4-homopiperidinonaphthyl-l )-propanol,

2-( 3-methyl-4-piperidinonaphthyl-l )-propanol,

2-( 3-chloro-4-piperidinonaphthyll )propanol,

(+)-2-( 4-piperidinonaphthyl-l )-propanol,

(-)-2-(4-piperidinonaphthyl-l )-propanol.

19. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-chloro-4-piperidinophenyl )-propyl-acetate,

2-( 3-bromo-4-piperidinophenyl)-propyl-acetate,

2-( 3-methyl-4-piperidinophenyl )-propyl-acetate,

2-( 3-methy]mercapto-4-piperidinophenyl )-propyl-acetate,

2-( 3-ethylmercapto-4-piperidinophenyl)-propyl-acetate,

2-(3-chloro-4piperidinophenyl)-propyl-propionate,

2-( 3-bromo-4-piperidinophenyl )-propyl-pripionate,

2-( 3-methyl-4-piperidinophenyl )propyl-propionate,

2-( 3-chloro-4-piperidinophenyl )-propyl-butyrate,

2-( 3-chloro-4-piperidinophenyl )-propyl-pa.lmitate.

20. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-chloro-4-piperidinophenyl )-propyl-stearate,

2-( 3-chloro-4-piperidinophenyl )-propyl-benzoate,

2-(4-piperidinonaphthyll )-propyl-acetate,

2-( 3-chloro-4-piperidinophenyl )-propyl-methanesulfonate,

2-( 3-chloro-4-piperidinophenyl )-propyl-p-toluenesulfonate, 2-( 3-chloro-4-piperidinophenyl )-propylmethyl ether, 2-( 3-chloro-4-piperidinophenyl)-propylethyl ether, 2-( 3-chloro-4-piperidinophenyl )-propyl-n-propyl ether, 2-( 3-chloro-4-piperidinophenyl )-propylisopropyl ether, 2-( 3-chloro-4-piperidinophenyl )-propyl-n-butyl ether. 21. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-( 3-bromo-4-piperidinophenyl )-propylmethyl ether, 2-( 3-methyl-4-piperidinophenyl )-propylmethyl ether, 2-( 3-ethylmercapto-4piperidinophenyl)-propylmethyl ether, 2-( 3-ethylmercapto-4-piperidinophenyl)-propylethyl ether, 2-( 3-chloro-4-piperidinophenyl )-propyl 2-hydroxyethyl ether, 2-( 3-chloro-4-piperidinophenyl )-propyl ether, 2-( 3-chloro-4-piperidinophenyl )-propylbenzyl ether, 2-( 3-chloro-4-piperidinophenyl )-propylallyl ether, 2(4-piperidinonaphthyl-l )-propylmethyl ether, 2-( 4-piperidinonaphthyl-l )-propylethyl ether, 2-( 4-piperidinonaphthyl-l )-propylpropyl ether, 2-( 4-piperidinonaphthyl-l )-propyl-n-butyl ether. 22. A member as defined by claim 1 wherein R is alkoxy of one to four carbon atoms.

23. A member as defined by claim 1 wherein R is saturated or unsaturated aliphatic, cycloaliphatic or aromatic hydrocarbon carbonyloxy of one to l 8 carbon atoms.

. A member as defined by claim 1 wherein R is alkylsulfonyloxy of one to six carbon atoms or hydrocarbon arylsulfonyloxy of six to 10 carbon atoms.

25. A compound of claim 1, 2-(3-chloro-4-piperidinophenyl )-propanol.

26. A compound of claim 1, 2-(4-piperidinonaphthyl-l propanol.

27. A compound of claim 1, 2-(3-chloro-4-piperidinophenyl)-propylmethyl ether.

28. A compound of claim I, 2-(3-bromo-4-piperidinophenyl)-propanol.

29. A compound of claim I, 2-(3methyl-4-piperidinophenyl )-pr0panol.

30. A compound of claim 1, 2-( 3-chloro-4-piperidinophenyl)-propyl butyrate.

31. A compound of claim 1, 2-(3-chloro-4-piperidinophenyl )-propyl acetate.

2-methoxyethyl 

2. A member as defined by claim 1 wherein R1 is OH.
 3. A member as defined by claim 1 wherein R2 is CH3.
 4. A member as defined by claim 1 wherein R3 is H,Cl, Br, Ch3, Ch3S or C2H5S with the provision that when R4 and R5 each represents H, R3 is other than H.
 5. A member as defined by claim 1 wherein R4 and R5 each represents H.
 6. A member as defined by claim 1 wherein R4 and R5 together represent -CH=CH-CH=CH-.
 7. A member as defined by claim 1 wherein Q represents piperidino.
 8. A member as defined by claim 1 wherein R3 is Cl, Br, CH3, CH3S or C2H5S, and R4 and R5 represEnt H.
 9. A member as defined by claim 1 wherein R3 is H, and R4 and R5 represent together -CH=CH-CH=CH-.
 10. A member as defined by claim 1 wherein R2 is CH3, R3 is Cl, Br, CH3, CH3S or C2H5S, R4 and R5 is H, and Q is piperidino.
 11. A member as defined by claim 1 wherein R2 is CH3, R3 is H, R4 and R5 together represent -CH=CH-CH=CH-, and Q represents piperidino.
 12. A member as defined by claim 1 wherein R1 is OH, R3 is Cl, Br, CH3, CH3S or C2H5S, and R4 and R5 are H.
 13. A member as defined by claim 1 wherein R1 is OH, R3 is H, and R4 and R5 together represent -CH=CH-CH=CH-.
 14. A member as defined by claim 1 wherein R1 is OH, R2 is CH3, R3 is Cl, Br, CH3, CH3S or C2H5S, R4 and R5 represent H, and Q is piperidino.
 15. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-chloro-4-piperidinophenyl)-ethanol, 2-(3-fluoro-4-piperidinophenyl)-propanol, 2-(3chloro-4-piperidinophenyl)-propanol, 2-(3-bromo-4-piperidinophenyl)-propanol, 2-(3-iodo-4-piperidinophenyl)-propanol, 2-(3-nitro-4-piperidinophenyl)-propanol, 2-(3-amino-4-piperidinophenyl)-propanol, 2-(3-methyl-4-piperidinophenyl)-propanol, 2-(3-ethyl-4-piperidinophenyl)-propanol, 2-(3-methylmercapto-4-piperidinophenyl)-propanol.
 16. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-ethylmercapto-4-piperidinophenyl)-propanol, (+)-2-(3-chloro-4-piperidinophenyl)-propanol, (-)-2-(3-chloro-4-piperidinophenyl)-propanol, (+)-2-(3-bromo-4-piperidinophenyl)-propanol, (-)-2-(3-bromo-4-piperidinophenyl)-propanol, (+)-2-(3-methyl-4-piperidinophenyl)propanol, (-)-2-(3-methyl-4-piperidinophenyl)-propanol, (+)-2-(3-ethylmercapto-4-piperidinophenyl)-propanol, (-)-2-(3-ethylmercapto-4-piperidinophenyl)-propanol, 2-(3-chloro-4-pyrrolidinophenyl)-propanol.
 17. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-bromo-4-pyrrolidinoOhenyl)-propanol, 2-(3-methyl-4-pyrrolidinophenyl)-propanol, 2-(3-amino-4-pyrrolidinophenyl)-propanol, 2-(3-methylmercapto-4-pyrrolidinophenyl)-propanol, 2-(3-ethylmercapto-4-pyrrolidinophenyl)-propanol, 2-(3-chloro-4-homopiperidinophenyl)-propanol, 2-(3-bromo-4-homopiperidinophenyl)-propanol, 2-(3-ethylmercapto-4-homopiperidinophenyl)-propanol, 2-(3-chloro-4-piperidinophenyl)-butanol, 2-(3-bromo-4-piperidinophenyl)-butanol.
 18. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-methyl-4-piperidinophenyl)-butanol, 2-(3-ethylmercapto-4-piperidinophenyl)-butanol, 2-(4-piperidinonaphthyl-1)-ethanol, 2-(4-piperidinonaphthyl-1)-propanol, 2-(4-pyrrolidinonaphthyl-1)-propanol, 2-(4-homopiperidinonaphthyl-1)-propanol, 2-(3-methyl-4-piperidinonaphthyl-1)-propanol, 2-(3-chloro-4-piperidinonaphthyl-1)-propanol, (+)-2-(4-piperidinonaphthyl-1)-propanol, (-)-2-(4-piperidinonaphthyl-1)-propanol.
 19. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-chloro-4-piperidinophenyl)-propyl-acetate, 2-(3-bromo-4-piperidinophenyl)-propyl-acetate, 2-(3-methyl-4-piperidinophenyl)-propyl-acetate, 2-(3-methylmercapto-4-piperidinophenyl)-propyl-acetate, 2-(3-ethylmercapto-4-piperidinophenyl)-propyl-acetate, 2-(3-chloro-4-piperidinophenyl)-propyl-propionate, 2-(3-bromo-4-piperidinophenyl)-propyl-pripionate, 2-(3-methyl-4-piperidinophenyl)propyl-propionate, 2-(3-chloro-4-piperidinophenyl)-propyl-butyrate, 2-(3-chloro-4-piperidinophenyl)-propyl-palmitate.
 20. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-chloro-4-piperidinophenyl)-propyl-stearate, 2-(3-chloro-4-piperidinophenyl)-propyl-benzoate, 2-(4-piperidinonaphthyl-1)-propyl-acetate, 2-(3-chloro-4-piperidinophenyl)-propyl-methanesulfonate, 2-(3-chloro-4-piperidinophenyl)-propyl-p-toluenesulfonate, 2-(3-chloro-4-piperidinophenyl)-propylmethyl ether, 2-(3-chloro-4-piperidinophenyl)-propylethyl ether, 2-(3-chloro-4-piperidinophenyl)-propyl-n-propyl ether, 2-(3-chloro-4-piperidinophenyl)-propylisopropyl ether, 2-(3-chloro-4-piperidinophenyl)-propyl-n-butyl ether.
 21. A member as defined by claim 1 wherein said member is selected from the group consisting of 2-(3-bromo-4-piperidinophenyl)-propylmethyl ether, 2-(3-methyl-4-piperidinophenyl)-propylmethyl ether, 2-(3-ethylmercapto-4-piperidinophenyl)-propylmethyl ether, 2-(3-ethylmercapto-4-piperidinophenyl)-propylethyl ether, 2-(3-chloro-4-piperidinophenyl)-propyl 2''-hydroxyethyl ether, 2-(3-chloro-4-piperidinophenyl)-propyl 2''-methoxyethyl ether, 2-(3-chloro-4-piperidinophenyl)-propylbenzyl ether, 2-(3-chloro-4-piperidinophenyl)-propylallyl ether, 2(4-piperidinonaphthyl-1)-propylmethyl ether, 2-(4-piperidinonaphthyl-1)-propylethyl ether, 2-(4-piperidinonaphthyl-1)-propylpropyl ether, 2-(4-piperidinonaphthyl-1)-propyl-n-butyl ether.
 22. A member as defined by claim 1 wherein R1 is alkoxy of one to four carbon atoms.
 23. A member as defined by claim 1 wherein R1 is saturated or unsaturated aliphatic, cycloaliphatic or aromatic hydrocarbon carbonyloxy of one to 18 carbon atoms.
 24. A member as defined by claim 1 wherein R1 is alkylsulfonyloxy of one to six carbon atoms or hydrocarbon arylsulfonyloxy of six to 10 carbon atoms.
 25. A compound of claim 1, 2-(3-chloro-4-piperidinophenyl)-propanol.
 26. A compound of claim 1, 2-(4-piperidinonaphthyl-1)-propanol.
 27. A compound of claim 1, 2-(3-chloro-4-piperidinophenyl)-propylmethyl ether.
 28. A compound of claim 1, 2-(3-bromo-4-piperidinophenyl)-propanol.
 29. A compound of claim 1, 2-(3methyl-4-piperidinophenyl)-propanol.
 30. A compound of claim 1, 2-(3-chloro-4-piperidinophenyl)-propyl butyrate.
 31. A compouNd of claim 1, 2-(3-chloro-4-piperidinophenyl)-propyl acetate. 